tag:blogger.com,1999:blog-64914230640231552642023-11-15T08:09:34.561-06:00TauopathiesTerry S. Singeltary Sr.http://www.blogger.com/profile/06986622967539963260noreply@blogger.comBlogger9125tag:blogger.com,1999:blog-6491423064023155264.post-54150933143508387802023-02-18T12:19:00.001-06:002023-02-18T12:19:39.147-06:00TAUOPATHIES, PICKS, AND PRIONS<p><span style="background-color: white; font-family: arial; font-size: 16px;">TAUOPATHIES, PICKS, AND PRIONS</span></p><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">NEURODEGENERATIVE DISEASES AND PRIONS</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">List of authors.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Stanley B. Prusiner, M.D.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">May 17, 2001</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">N Engl J Med 2001; 344:1516-1526</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">DOI: 10.1056/NEJM200105173442006</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Article Figures/Media 119 References 584 Citing Articles Related Articles</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Twenty-five years ago, little was known about the causes of neurodegenerative diseases. Now, however, it is clear that they result from abnormalities in the processing of proteins. In each of these diseases, defective processing causes the accumulation of one or more specific neuronal proteins. Of all the laboratory research on neurodegenerative diseases, the studies that led to the discovery of prions have yielded the most unexpected findings. The idea that a protein can act as an infectious pathogen and cause degeneration of the central nervous system was accepted only after a long and arduous battle.1 The concept of prions not only has provided an explanation of how a disease can be both infectious and genetic, but has also revealed hitherto unknown kinds of neurologic diseases. This review presents a unifying concept of degenerative brain diseases, based on what we have learned about prions.2</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Table 1. </div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">nejm200105173442006_t1.jpeg</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Prevalence of Neurodegenerative Diseases in the United States in 2000.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Alzheimer's disease is the most common neurodegenerative disorder (Table 1). In the United States, approximately 4 million people have Alzheimer's disease, and approximately 1 million have Parkinson's disease.3-5Much less common are amyotrophic lateral sclerosis, frontotemporal dementia, prion diseases, Huntington's disease, and spinocerebellar ataxias.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">With the increase in life expectancy, there has been concern about the incidence of Alzheimer's and Parkinson's diseases. Among persons who are 60 years old, the prevalence of Alzheimer's disease is approximately 1 in 10,000, but among those who are 85 years old, it is greater than 1 in 3.6 These data suggest that by 2025, there will be more than 10 million cases of Alzheimer's disease in the United States, and by 2050, the number will approach 20 million.4 The annual cost associated with Alzheimer's disease in the United States is estimated at $200 billion. Age is also the most important risk factor for Parkinson's disease. Nearly 50 percent of persons who are 85 years old also have at least one symptom or sign of parkinsonism.7</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Virtually all neurodegenerative disorders involve abnormal processing of neuronal proteins. The aberrant mechanism can entail a misfolding of proteins, altered post-translational modification of newly synthesized proteins, abnormal proteolytic cleavage, anomalous gene splicing, improper expression, or diminished clearance of degraded protein. Misprocessed proteins often accumulate because the cellular mechanisms for removing them are ineffective. The particular protein that is improperly processed determines the malfunction of distinct sets of neurons and thus the clinical manifestations of the disease.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Prions</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Prions are infectious proteins. In mammals, prions reproduce by recruiting normal cellular prion protein (PrPC) and stimulating its conversion to the disease-causing (scrapie) isoform (PrPSc). A major feature that distinguishes prions from viruses is that PrPSc is encoded by a chromosomal gene.8 Limited proteolysis of PrPSc produces a smaller, protease-resistant molecule of approximately 142 amino acids, designated PrP 27–30, which polymerizes into amyloid.9</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Figure 1. </div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">nejm200105173442006_f1.jpeg</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Structures of Prion Protein (PrP) Isoforms.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">The polypeptide chains of PrPC and PrPSc are identical in composition but differ in their three-dimensional, folded structures (conformations). PrPC is rich in α-helixes (spiral-like formations of amino acids) and has little β-sheet (flattened strands of amino acids), whereas PrPSc is less rich in α-helixes and has much more β-sheet.10 There is evidence that PrPC has three α-helixes and two short β-strands; in contrast, a plausible model suggests that PrPScmay have only two α-helixes and more β-strands (Figure 1).11,12 This structural transition from α-helixes to β-sheet in PrP is the fundamental event underlying prion diseases.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Four new concepts have emerged from studies of prions. First, prions are the only known example of infectious pathogens that are devoid of nucleic acid. All other infectious agents possess genomes composed of either RNA or DNA that direct the synthesis of their progeny. Second, prion diseases may be manifested as infectious, genetic, or sporadic disorders. No other group of illnesses with a single cause has such a wide spectrum of clinical manifestations. Third, prion diseases result from the accumulation of PrPSc, which has a substantially different conformation from that of its precursor, PrPC. Fourth, PrPSc can have a variety of conformations, each of which seems to be associated with a specific disease. How a particular conformation of PrPSc is imparted to PrPC during replication in order to produce a nascent PrPSc with the same conformation is unknown. The factors that determine the site in the central nervous system where a particular PrPSc is deposited are also not known.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Prion Diseases</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Prion diseases have a broad spectrum of clinical manifestations, including dementia, ataxia, insomnia, paraplegia, paresthesias, and deviant behavior.13 Neuropathological findings range from an absence of atrophy to widespread atrophy, from minimal to widespread neuronal loss, from sparse to widespread vacuolation or spongiform changes, from mild to severe reactive astrocytic gliosis, and from an absence of PrP amyloid plaques to an abundance of plaques.14None of these findings except the presence of PrP amyloid plaques is unequivocally diagnostic of a prion disease.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Table 2. </div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">nejm200105173442006_t2.jpeg</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Pathogenetic Features of Prion Diseases.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">The sporadic form of Creutzfeldt–Jakob disease, which is typically manifested as dementia and myoclonus, accounts for approximately 85 percent of all cases of prion disease in humans, whereas infectious and inherited prion diseases account for the rest. Familial Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia are all dominantly inherited prion diseases caused by mutations in the prion protein gene (PRNP) (Table 2).15-19 Experiments that showed transmission of these diseases by filtrates of brain from familial cases20,21 were wrongly attributed to a virus. There is no Creutzfeldt–Jakob disease virus, and familial prion diseases are caused by mutations in PRNP. 22</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">EPIDEMIOLOGIC FEATURES</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Prions cause Creutzfeldt–Jakob disease in humans throughout the world. The incidence of sporadic Creutzfeldt–Jakob disease is approximately 1 case per 1 million population,23 but among persons between the ages of 60 and 74 years, the incidence is nearly 5 per 1 million.24 Cases in patients as young as 17 years and as old as 83 have been recorded.23,25 Creutzfeldt–Jakob disease is relentlessly progressive and usually causes death within a year after its onset. Each geographic cluster of cases of prion disease was initially thought to be a manifestation of viral communicability,26 but each was later shown to be due to a PRNP gene mutation except for new variant Creutzfeldt–Jakob disease.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">NEUROPATHOLOGICAL FEATURES</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Figure 2. </div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">nejm200105173442006_f2.jpeg</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Neuropathological Features of Prion Diseases in Humans.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">There are often no recognizable gross abnormalities in the brains of patients with Creutzfeldt–Jakob disease. Patients who survive for several years have variable degrees of cerebral atrophy. The microscopical features of Creutzfeldt–Jakob disease are spongiform degeneration and astrogliosis (Figure 2A and Figure 2B).27</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Amyloid plaques occur in approximately 10 percent of cases of Creutzfeldt–Jakob disease. These plaques are positive for antibodies against PrPSc on immunohistochemical staining.28,29 The amyloid plaques in patients with Gerstmann–Sträussler–Scheinker disease consist of a dense core of amyloid surrounded by smaller globules of amyloid (Figure 2). A characteristic feature of new variant Creutzfeldt–Jakob disease is the presence of “florid plaques” composed of a core of PrPSc amyloid surrounded by vacuoles (Figure 2E and Figure 2F).</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">STRAINS OF PRIONS</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">The existence of prion strains raises the question of how heritable biologic information can be encrypted in a molecule other than nucleic acid.30-32 Strains of prions have been defined by the rapidity with which they cause central nervous system disease and by the distribution of neuronal vacuolation.30 Patterns of PrPSc deposition have also been used to characterize these strains.33,34There is mounting evidence that the diversity of prions is enciphered in the conformation of the PrPSc protein.35-39 Studies involving the transmission of fatal familial insomnia and familial Creutzfeldt–Jakob disease to mice expressing a chimeric human–mouse PrP transgene have shown that the tertiary and quaternary structure of PrPSc contains strain-specific information.37Studies of patients with fatal sporadic insomnia have extended these findings,40 making it clear that PrPSc acts as a template for the conversion of PrPC into nascent PrPSc.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">SPORADIC, GENETIC, AND INFECTIOUS FORMS OF PRION DISEASE</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Sporadic prion diseases might be initiated by a somatic mutation and in this respect might develop in a manner similar to prion diseases caused by germ-line mutations. In this situation, the mutant PrPSc must be capable of recruiting wild-type PrPC, a process that may occur with some mutations but is unlikely with others.41 Alternatively, the activation barrier separating wild-type PrPC from PrPSc may be crossed on rare occasions in the context of a large population of people.42 Twenty mutations in the human PRNP gene have been found to segregate with inherited prion diseases.43 Missense mutations and expansions in the octapeptide-repeat region of the gene cause familial prion diseases.15-19</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Although infectious prion diseases constitute less than 1 percent of all cases of prion disease, the circumstances surrounding the transmission of these infectious illnesses are often dramatic (Table 2). Ritualistic cannibalism has resulted in the transmission of kuru among the Fore people of New Guinea, industrial cannibalism has been responsible for bovine spongiform encephalopathy (BSE), or “mad cow disease,” in Europe, and an increasing number of patients have contracted new variant Creutzfeldt–Jakob disease from prion-tainted beef products.13</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">The restricted geographic and temporal distribution of cases of new variant Creutzfeldt–Jakob disease raises the possibility that BSE prions have been transmitted to humans. Although over 100 cases of new variant Creutzfeldt–Jakob disease have been recorded,44,45 no dietary habits distinguish patients with this disease from apparently healthy persons. Moreover, it is unclear why teenagers and young adults seem to be particularly susceptible to the disease. These cases may mark the start of an epidemic of prion disease in Great Britain like those of BSE and kuru, or the number of cases of new variant Creutzfeldt–Jakob disease may remain small, as with iatrogenic Creutzfeldt–Jakob disease caused by cadaveric human growth hormone.46</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">The most compelling evidence that new variant Creutzfeldt–Jakob disease is caused by BSE prions comes from studies of mice expressing the bovine PrP transgene.47 The incubation times, neuropathological features, and patterns of PrPSc deposition in these transgenic mice are the same whether the inoculate originated from the brains of cattle with BSE or from humans with new variant Creutzfeldt–Jakob disease.47 The origin of BSE is still obscure, although epidemiologic studies indicate that BSE probably arose from a single point source in the southwest of England in the 1970s.48 It probably originated from a rare case of prion disease in either sheep (Scott M, Prusiner SB: unpublished data) or cattle.48 Once established, the disease was spread in cattle by ingestion of prion-contaminated meat and bone meal.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">The accidental transmission of Creutzfeldt–Jakob disease to humans appears to have occurred with corneal transplantation49 and use of contaminated electroencephalographic electrodes.50The same improperly decontaminated electrodes that had caused Creutzfeldt–Jakob disease in two young patients with intractable epilepsy were found to cause Creutzfeldt–Jakob disease in a chimpanzee 18 months after their implantation in the animal.51 More than 70 cases of Creutzfeldt–Jakob disease associated with the implantation of dura mater grafts have been recorded.52 One case occurred after the repair of a perforated eardrum with a pericardial graft.53Prion-contaminated human growth hormone preparations derived from human pituitary tissue have caused fatal cerebellar disorders with dementia in more than 120 patients ranging in age from 10 to 41 years.13,54,55 Four cases of Creutzfeldt–Jakob disease have occurred in women who received human pituitary gonadotropin.56 Polymorphisms influence the susceptibility to sporadic, inherited, and infectious forms of prion disease. Dominant negative alleles in approximately 12 percent of the Japanese population57encode for lysine at position 219 and interfere with the conversion of wild-type PrPC into PrPSc.58,59 Dominant negative inhibition of prion replication has also been found in sheep, with a substitution of the basic residue arginine at position 171.60,61</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Other Neurodegenerative Diseases</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Like cases of the prion diseases, most cases of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia are sporadic; 10 percent or less are inherited. Although age is the most important risk factor in all these sporadic forms of disease, the factors that initiate neurodegeneration remain unknown. In the prion diseases, the initial formation of PrPSc leads to an exponential increase in the protein, which can be readily transmitted to another host. In the other neurodegenerative diseases, the events that lead to the production of aberrantly processed proteins, as well as the driving forces that sustain their accumulation, are unknown. It is important to stress that in contrast to the prion diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia are not infectious and have not been transmitted to laboratory animals.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">ALZHEIMER'S DISEASE</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Table 3. </div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">nejm200105173442006_t3.jpeg</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Protein Deposition in Neurodegenerative Diseases.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Table 4. </div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">nejm200105173442006_t4.jpeg</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Mutant Genes in Familial Neurodegenerative Diseases.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Aβ-amyloid plaques and neurofibrillary tangles are found in both sporadic and inherited forms of Alzheimer's disease (Table 3). Like familial prion diseases, familial Alzheimer's disease has an autosomal dominant pattern of inheritance. Familial Alzheimer's disease can be caused by a mutation in the gene for amyloid precursor protein (APP), presenilin 1, or presenilin 2 (Table 4).62 Cleavage of amyloid precursor protein at residue 671 by β-secretase and at either residue 711 or residue 713 by γ-secretase produces Aβ(1–40) and Aβ(1–42), respectively. Aβ(1–42) forms amyloid fibrils readily and is thought to cause central nervous system dysfunction before it is deposited in plaques.63-65 Presenilin 1 and presenilin 2 may form complexes with at least one other protein, nicastrin, a transmembrane neuronal glycoprotein, and these complexes may contribute to the production of Aβ(1–42).66</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">The age of onset of both sporadic and familial forms of Alzheimer's disease is modulated by allelic variants of apolipoprotein E.67 Three alternative allelic products of apolipoprotein E, denoted ε2, ε3, and ε4, differ at amino acid residues 112 and 158. In many persons with two ε4 alleles, Alzheimer's disease develops at least a decade before it does in those with two copies of ε2, and ε3 is associated with an onset of disease at an intermediate age.68</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">FRONTOTEMPORAL DEMENTIA AND PICK'S DISEASE</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Mutations in the tau gene, which codes for tau, a protein associated with microtubules, cause inherited forms of frontotemporal dementia and Pick's disease.69-71 As with Alzheimer's disease, about 90 percent of cases of frontotemporal dementia are sporadic, and the rest are familial. Straight filaments composed of hyperphosphorylated mutant tau have been found in the brains of patients with familial frontotemporal dementia (Table 3).72 In some cases, neurofibrillary tangles composed of paired helical filaments have been found; the formation of these filaments seems to depend on the specific mutation and on the specific isoform of the protein (Table 4).73In sporadic cases of frontotemporal dementia, aggregates of tau are uncommon. Approximately 15 percent of patients with frontotemporal dementia have Pick bodies,74 which are intracellular collections of partially degraded (ubiquinated) tau fibrils in the brain.75 As with frontotemporal dementia, most cases of Pick's disease are sporadic. Other disorders caused by the misprocessing of tau include progressive supranuclear palsy, progressive subcortical gliosis, and corticobasal degeneration.73,75-77</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">PARKINSON'S DISEASE</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Most cases of Parkinson's disease are sporadic,78,79 but both sporadic and familial forms of the disease are characterized by protein deposits in the central nervous system. Mutations in the gene for α-synuclein have been found in patients with familial Parkinson's disease.80 In both sporadic and familial cases, antibodies to α-synuclein, a presynaptic intracellular protein, stain Lewy bodies in neurons of the substantia nigra.81 Whereas the inheritance of Parkinson's disease due to mutations in the α-synuclein gene is autosomal dominant, a childhood form of the disease due to mutations in the gene for ubiquitin–protein ligase (parkin) is a recessive disorder (Table 4).82 Parkin seems to promote the degradation of certain neuronal proteins, and selective nitration of α-synuclein has been observed in Lewy bodies.83</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Parkinson's disease in older persons is associated with a high incidence of dementia.84 At autopsy, the brains of such patients often have the neuropathological hallmarks of both Alzheimer's disease and Parkinson's disease. Immunohistochemical studies showing the presence of α-synuclein in cortical Lewy bodies have helped resolve the conundrum of how a patient could have insufficient numbers of plaques and neurofibrillary tangles for the diagnosis of Alzheimer's disease but still have dementia. The presence of these α-synuclein deposits, alone or in combination with changes that are characteristic of Alzheimer's disease, may be the second most common form of neurodegeneration, accounting for 20 to 30 percent of cases of dementia among persons over the age of 60 years.85,86 A small number of younger persons with Parkinson's disease also have dementia due to diffuse Lewy body disease.87</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">AMYOTROPHIC LATERAL SCLEROSIS</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Although most cases of amyotrophic lateral sclerosis are sporadic, familial cases have been identified.88-90 In approximately 20 percent of familial cases of amyotrophic lateral sclerosis, there are mutations in the gene for cytoplasmic superoxide dismutase type 1 (SOD1) (Table 4).91Moreover, deposits of SOD1 in the central nervous system have been found in both sporadic and familial cases of amyotrophic lateral sclerosis.92 Although in some cases abnormal collections of neurofilaments have been seen in degenerating motor neurons, no familial cases have been shown to be due to mutations in neurofilament genes.92</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">HUNTINGTON'S DISEASE AND SPINOCEREBELLAR ATAXIAS</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Unlike Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, and the prion diseases, which in most cases are sporadic, all cases of Huntington's disease and of spinocerebellar ataxia are caused by expanded polyglutamine repeats (Table 4).93-95 But these diseases are similar to the inherited forms of Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, and the prion diseases in that they are usually manifested as neurologic deficits in adulthood, even though the expression of the mutant gene products in the central nervous system begins early in life. Childhood forms of Huntington's disease and spinocerebellar ataxia are known to be due to large expansions of the causative triplet repeats.94,96,97</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">TRANSGENIC MOUSE MODELS</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Although virtually every facet of the human and animal prion diseases has been reproduced in transgenic mice, attempts to develop transgenic models for the other neurodegenerative diseases have proved more difficult. Despite the lack of perfect transgenic models for Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementias, Huntington's disease, and the spinocerebellar ataxias, many aspects of these human disorders have been reproduced. Mice expressing transgenes carrying mutations found in the inherited forms of these neurodegenerative diseases develop disorders with many of the neuropathological features that characterize the corresponding human illnesses (Table 3 and Table 4).</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Diagnostic Tests</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">There is an urgent need for a rapid, antemortem test for prions in humans and livestock. A highly sensitive quantitative immunoassay has been developed on the basis of antigens that are exposed in PrPC but buried in PrPSc. Unlike earlier immunoassays for PrPSc, this conformation-dependent immunoassay does not require limited proteolysis to hydrolyze PrPC before the protease-resistant core of PrPSc (PrP 27–30) is measured.38 This assay has been used to identify a new form of PrPSc, which is protease-sensitive (sPrPSc).</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">A diagnostic test would be valuable for distinguishing between early Alzheimer's disease and depression in older persons, since both disorders are so common. In Alzheimer's disease, frontotemporal dementia, Parkinson's disease, and the prion diseases, computed tomography or magnetic resonance imaging may show normal findings or cortical atrophy. In patients with Alzheimer's disease, widespread atrophy with enlarged ventricles is often seen, especially late in the disease, but this finding is not diagnostic. Many elderly persons with normal cognition have similar radiographic findings.98,99 Although many patients with Creutzfeldt–Jakob disease have elevated levels of protein 14-3-3 in cerebrospinal fluid, this finding is not specific for the diagnosis.100,101 Attempts to measure Aβ(1–40) in blood and urine as diagnostic tests have been unrewarding,102 but the use of fluorescence correlation spectroscopy to measure Aβ(1–40) in cerebrospinal fluid may provide a reliable diagnostic test for Alzheimer's disease.103</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Whereas electroencephalographic studies are not useful for the diagnosis of Alzheimer's disease, frontotemporal dementia, or Parkinson's disease, they are often useful for the diagnosis of Creutzfeldt–Jakob disease. Repetitive, high-voltage, triphasic and polyphasic sharp discharges are seen in most advanced cases of Creutzfeldt–Jakob disease, but their presence is often transient.25,101,104,105 As the disease progresses, normal background rhythms become fragmentary and slower.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Hashimoto's thyroiditis should always be considered in the differential diagnosis of Creutzfeldt–Jakob disease,106 since the former disorder is a treatable autoimmune disease whereas Creutzfeldt–Jakob disease is not. The clinical and neuropathological findings in these two disorders can be quite similar, raising the possibility that protein misprocessing underlies both degenerative and autoimmune diseases.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Prevention and Treatment</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">With the exception of levodopa, which ameliorates the symptoms of Parkinson's disease but does not halt the underlying degeneration, there are no effective therapies for neurodegenerative diseases. The history of successful attempts to prevent or reverse protein misprocessing is extremely limited.107 Developing new drugs directed to specific regions of the central nervous system will be challenging.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">PREVENTING ABNORMAL PROCESSING OF PROTEINS AND ENHANCING THEIR CLEARANCE</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Structure-based drug design based on dominant negative inhibition of prion formation has resulted in the development of several compounds.108 However, the task of exchanging polypeptide scaffolds for small heterocyclic structures without the loss of biologic activity remains difficult. Whether this approach to preventing the aberrant processing of proteins will lead to the development of new treatments for Alzheimer's and Parkinson's diseases, as well as other neurodegenerative disorders, remains to be established.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Several compounds can eliminate prions from cultured cells. A class of compounds known as “dendrimers” seems particularly effective in this regard.109 Some drugs delay the onset of disease in animals that have been inoculated with prions if the drugs are given around the time of the inoculation.110 A novel approach to treating Alzheimer's disease has been developed in transgenic mice that overexpress a mutant APP gene. Immunization of these mice with the Aβ peptide or injection of antibodies to Aβ reduces plaque formation.111 Whether this approach will prove fruitful in patients is unknown.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">REPLACEMENT THERAPY</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Because the neurodegeneration in Parkinson's disease is confined largely to the substantia nigra, especially early in the disease process, replacement therapy with levodopa has proved useful; in many patients, however, the disease eventually becomes refractory to levodopa.112 Similar approaches to the treatment of Alzheimer's disease have been disappointing, primarily because the disease process is so widespread. Similarly, the widespread neuropathological changes in amyotrophic lateral sclerosis, frontotemporal dementia, and prion diseases make it unlikely that replacement therapy will be successful.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Speculation on the Spectrum of Degenerative Diseases</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">It is tempting to speculate that abnormal processing of neuronal proteins also occurs in other diseases of the central nervous system, such as schizophrenia, bipolar disorders, autism, and narcolepsy.113 Most cases of these diseases are sporadic, but a substantial minority appear to be familial. The absence of neuropathological changes in these conditions has impeded phenotypic analysis. In a group of patients with inherited frontotemporal dementia who have a mutation in the tau gene, alcoholism and Parkinson's disease are prominent features.114</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Whether multiple sclerosis is also the result of defective processing of brain proteins is unknown.115 The immune system features prominently in the pathogenesis of multiple sclerosis, and it is often argued that this disease is a T-cell–mediated, autoimmune disorder. Antibody-mediated demyelination has been found in some cases of multiple sclerosis,116 and in others, degeneration of oligodendrocytes has been observed, with little or no evidence of immune-mediated damage.117 Perhaps ulcerative colitis, Crohn's disease, rheumatoid arthritis, type 1 diabetes mellitus, and systemic lupus erythematosus ought to be considered disorders of protein processing in which misfolded proteins evoke an autoimmune response.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">The systemic amyloidoses share important features with the neurodegenerative diseases. In primary amyloidosis, immunoglobulin light chains form amyloid deposits that can cause cardiomyopathy, renal failure, and polyneuropathy.118 In response to chronic inflammatory diseases, the serum amyloid A protein is cleaved and forms the amyloid A protein, which is deposited as fibrils in the kidney, liver, and spleen. The most common form of systemic hereditary amyloidosis is caused by the deposition of mutant transthyretin. Also noteworthy are amylin deposits in the β-islet cells of patients with type 2 diabetes mellitus. These deposits contain amyloid fibrils that are composed of the amylin protein.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">The Future</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">As life expectancy continues to increase, the burden of degenerative diseases is growing. Developing effective means of preventing these disorders and of treating them when they do occur is a paramount challenge. The problems caused by Alzheimer's disease and Parkinson's disease are already so great that if the prevalence of these maladies continues to increase in accordance with the changing demographic characteristics of the world population, they will bankrupt both developed and developing countries over the next 50 years. It is remarkable to think that by the year 2025, more than 65 percent of persons over the age of 65 years will be living in countries that are now designated as developing countries.119 Unless effective methods of prevention and treatment are developed, this enormous population of people will be subjected to the same risks of Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders as are older persons currently living in the most affluent countries.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Over the past two decades, remarkable progress has been made in elucidating the causes of neurodegenerative diseases, and the time has come to intensify the search for drug targets and for compounds that interrupt the disease processes. Drugs that block the mishandling of a particular protein may be most effective for certain disorders; for others, drugs that enhance the clearance of an aberrant protein or fragment may prove most useful. Regardless of the therapeutic approach, accurate, early detection of neurodegeneration will be extremely important so that drugs can be given before substantial damage to the central nervous system has occurred. However, the enormity of these tasks — developing useful diagnostic tests and discovering effective therapies — should not be underestimated.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Presented as the 110th Shattuck Lecture to the Annual Meeting of the Massachusetts Medical Society, Boston, May 20, 2000.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Supported by grants from the National Institutes of Health (NS14069, AG02132, and AG10770), the American Health Assistance Foundation, and the Leila and Harold Mathers Foundation.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">I am indebted to Drs. Fred Cohen, Stephen DeArmond, Kirk Wilhemsen, Robert Edwards, Warren Olanow, Steve Finkbiener, and Steve Hauser for their valuable comments and suggestions; to Dr. Fred Cohen for preparation of the PrP structural illustrations; and to Dr. Stephen DeArmond for preparation of the photomicrographs.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Author Affiliations</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">From the Institute for Neurodegenerative Diseases and the Departments of Neurology and of Biochemistry and Biophysics, University of California, San Francisco.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Address reprint requests to Dr. Prusiner at the Institute for Neurodegenerative Diseases, Box 0518, University of California, San Francisco, CA 94143-0518. </div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;"><a href="https://www.nejm.org/doi/full/10.1056/NEJM200105173442006" rel="nofollow" style="color: #196ad4;" target="_blank">https://www.nejm.org/doi/full/10.1056/NEJM200105173442006</a></div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">References <a href="https://www.nejm.org/doi/full/10.1056/NEJM200105173442006" rel="nofollow" style="color: #196ad4;" target="_blank">https://www.nejm.org/doi/full/10.1056/NEJM200105173442006</a></div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Stanley PRUSINER </div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Stanley Prusiner Portrait. </div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Senior author Stanley B. Prusiner, MD, director of the UCSF Institute for Neurodegenerative Diseases and professor in the departments of Neurology and of Biochemistry and Biophysics. Image courtesy UCSF Institute for Neurodegenerative Diseases.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">“I believe this shows beyond a shadow of a doubt that amyloid beta and tau are both prions, and that Alzheimer’s disease is a double-prion disorder in which these two rogue proteins together destroy the brain,” </div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">said Stanley Prusiner, MD, the study’s senior author and director of the UCSF Institute for Neurodegenerative Diseases, part of the UCSF Weill Institute for Neurosciences. </div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">“The fact that prion levels also appear linked to patient longevity should change how we think about the way forward for developing treatments for the disease. We need a sea change in Alzheimer’s disease research, and that is what this paper does. This paper might catalyze a major change in AD research.” </div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">J Neurochem. 2016 Aug;138 Suppl 1(Suppl Suppl 1):163-83. doi: 10.1111/jnc.13668.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Prion-like propagation as a pathogenic principle in frontotemporal dementia</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;"><a href="https://www.ucsf.edu/news/2019/05/414326/alzheimers-disease-double-prion-disorder-study-shows" rel="nofollow" style="color: #196ad4;" target="_blank">https://www.ucsf.edu/news/2019/05/414326/alzheimers-disease-double-prion-disorder-study-shows</a></div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Prion-like propagation as a pathogenic principle in frontotemporal dementia</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/27502124/" rel="nofollow" style="color: #196ad4;" target="_blank">https://pubmed.ncbi.nlm.nih.gov/27502124/</a></div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Acta Neuropathol. 2021; 142(2): 227–241.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Published online 2021 Jun 14. doi: 10.1007/s00401-021-02336-w</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">PMCID: PMC8270882</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">NIHMSID: NIHMS1721892</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">PMID: 34128081</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Structure of Tau filaments in Prion protein amyloidoses</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Grace I. Hallinan,#1 Md Rejaul Hoq,#2 Manali Ghosh,2 Frank S. Vago,2 Anllely Fernandez,1 Holly J. Garringer,1 Ruben Vidal,corresponding author1,3 Wen Jiang,corresponding author2 and Bernardino Ghetticorresponding author1</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Abstract</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) with a nonsense mutation in the PRNP gene that leads to early termination of translation of PrP (Q160Ter or Q160X), and Gerstmann–Sträussler–Scheinker (GSS) disease, with a missense mutation in the PRNP gene that leads to an amino acid substitution at residue 198 (F198S) of PrP. The clinical and neuropathologic phenotypes associated with these two mutations in PRNP are different; however, the neuropathologic analyses of these two genetic variants have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA (Q160X) and GSS (F198S) are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA (Q160X), Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS (F198S), only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA (Q160X) and GSS (F198S) brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA (Q160X) and GSS (F198S) are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of extracellular amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">snip...</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Amyloid and Tau aggregates coexist in AD and in other diseases in addition to the group of the PrP Amyloidoses [22], two of which are reported here. In fact, in other hereditary cerebral amyloid diseases such as Familial British dementia (FBD) [34, 59] and Familial Danish dementia (FDD) [35, 60], a severe neurofibrillary Tau pathology occurs. Our study shows for the first time that Tau fibrils deposited in the brain of individuals with a brain amyloidosis other than AD are biochemically, antigenically, and structurally identical. Moreover, a recent study shows that Tau fibrils isolated from the brain of individuals with FBD and FDD are also structurally identical to those in AD [56]. The co-existence of Tau aggregates with different types of amyloids suggests a common mechanism through which amyloids, whether Aβ in AD, APrP in Prion diseases, ABri in FBD or ADan in FDD, trigger aggregation of Tau, resulting in Tau filaments with identical structure at their core (Fig. 5). Furthermore, Tau from the brains of patients with AD, GSS (F198S), and PrP-CAA (Q160X) have similar seeding activities in vitro, as has been also seen for brain homogenates from AD and PART [38]. For AD, it has been proposed that Aβ provides a crucial element toward Tau aggregation [4, 30]. This hypothesis has been supported by genetic forms of AD due to mutations in the AβPP, PSEN1, and PSEN2 genes that consistently alter the metabolism of Aβ, with a consequent Tau hyperphosphorylation and formation of Tau aggregates in vitro and in vivo [15, 19, 28]. Altered Tau metabolism in association with APrP has also been observed in in vitro studies [42] and in vivo in mouse models [48, 50]. By determining the structure of the core of Tau filaments from diseases caused by two distinct PRNP mutations, F198S and Q160X, to be identical to the core of Tau filaments from AD, we uncover potential links between amyloid proteins and the resulting Tau aggregation. Structural data are urgently needed for the identification of specific ligands for in vivo imaging of Tau aggregates in a wide range of neurodegenerative diseases.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270882/" rel="nofollow" style="color: #196ad4;" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270882/</a></div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Prog Mol Biol Transl Sci . 2020;175:239-259. doi: 10.1016/bs.pmbts.2020.08.003. Epub 2020 Sep 8.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Tau proteinopathies and the prion concept</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Michel Goedert 1 Affiliations expand</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">PMID: 32958235 DOI: 10.1016/bs.pmbts.2020.08.003</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Abstract</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">The ordered assembly of a small number of proteins into amyloid filaments is central to age-related neurodegenerative diseases. Tau is the most commonly affected of these proteins. In sporadic diseases, assemblies of tau form in a stochastic manner in certain brain regions, from where they appear to spread in a deterministic way, giving rise to disease symptoms. Over the past decade, multiple lines of evidence have shown that assembled tau behaves like a prion. More recently, electron cryo-microscopy of tau filaments has shown that distinct conformers are present in different diseases, with no inter-individual variation for a given disease.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;">Keywords: Alzheimer's disease; Chronic traumatic encephalopathy; Corticobasal degeneration; Electron cryo-microscopy; Pick's disease; Prion-like; Tau proteinopathy.</div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;"><a href="https://pubmed.ncbi.nlm.nih.gov/32958235/" rel="nofollow" style="color: #196ad4;" target="_blank">https://pubmed.ncbi.nlm.nih.gov/32958235/</a><br /></div><div style="background-color: white; font-family: arial; font-size: 16px;"><br /></div><div data-setdir="false" dir="ltr" style="background-color: white; font-family: arial; font-size: 16px;"><div><div>Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells</div><div><br /></div><div>Amanda L. Woerman, Atsushi Aoyagi, Smita Patel, +6, and Stanley B. Prusiner stanley.prusiner@ucsf.eduAuthors Info & Affiliations Contributed by Stanley B. Prusiner, October 6, 2016 (sent for review August 5, 2016; reviewed by Robert H. Brown Jr. and David Westaway)</div><div><br /></div><div>November 28, 2016</div><div><br /></div><div>113 (50) E8187-E8196</div><div><br /></div><div><a href="https://doi.org/10.1073/pnas.1616344113" rel="nofollow" style="color: #196ad4;" target="_blank">https://doi.org/10.1073/pnas.1616344113</a></div><div><br /></div><div>Significance</div><div><br /></div><div>The progressive nature of neurodegenerative diseases is due to the spread of prions, misfolded infectious proteins, in the brain. In tauopathies, the protein tau misfolds, causing several diseases, including Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). Here we created a panel of mammalian cell lines expressing a fragment of tau fused to yellow fluorescent protein. Each cell line selectively detects tau prions that are misfolded into self-propagating conformations; such cells permit identification of minute differences among tauopathies. For example, tau prions in AD and CTE are distinct from prions in other tauopathies such as Pick’s disease and progressive supranuclear palsy. These insights are likely to contribute to the development of future therapeutics.</div><div><br /></div><div><a href="https://www.pnas.org/doi/full/10.1073/pnas.1616344113" rel="nofollow" style="color: #196ad4;" target="_blank">https://www.pnas.org/doi/full/10.1073/pnas.1616344113</a></div><div><br /></div><div>Aβ and tau prions feature in the neuropathogenesis of Down syndrome</div><div><br /></div><div>Carlo Condello carlo.condello@ucsf.edu, Alison M. Maxwell, Erika Castillo https://orcid.org/0000-0003-2492-901X, +9, and Stanley B. Prusiner </div><div><br /></div><div>https://orcid.org/0000-0003-1955-5498 stanley.prusiner@ucsf.eduAuthors Info & Affiliations</div><div><br /></div><div>Contributed by Stanley Prusiner; received August 1, 2022; accepted September 27, 2022; reviewed by Robert Brown Jr. and Neil Cashman.</div><div><br /></div><div>November 7, 2022</div><div><br /></div><div>119 (46) e2212954119</div><div><br /></div><div><a href="https://doi.org/10.1073/pnas.2212954119" rel="nofollow" style="color: #196ad4;" target="_blank">https://doi.org/10.1073/pnas.2212954119</a></div><div><br /></div><div>Significance</div><div><br /></div><div>Approximately 5.4 million people worldwide have Down syndrome (DS), which is caused by trisomy of chromosome 21 (Chr21). The APP gene is one of approximately 250 protein-coding genes located on Chr21, and its duplication is associated with elevated Aβ production and increased incidence of Alzheimer’s disease (AD) neuropathology in most aged individuals with DS. Since AD brains have plaques composed of Aβ prions and neurofibrillary tangles composed of tau prions, we asked if DS brains have both Aβ and tau prions. We found that the age-dependent kinetics of Aβ and tau prions are distinct in DS and could even be detected in a 19-y-old individual. Whether DS is an ideal model for assessing efficacy of putative AD therapeutics remains unknown.</div><div><br /></div><div>Abstract</div><div><br /></div><div>Down syndrome (DS) is caused by the triplication of chromosome 21 and is the most common chromosomal disorder in humans. Those individuals with DS who live beyond age 40 y develop a progressive dementia that is similar to Alzheimer’s disease (AD). Both DS and AD brains exhibit numerous extracellular amyloid plaques composed of Aβ and intracellular neurofibrillary tangles composed of tau. Since AD is a double-prion disorder, we asked if both Aβ and tau prions feature in DS. Frozen brains from people with DS, familial AD (fAD), sporadic AD (sAD), and age-matched controls were procured from brain biorepositories. We selectively precipitated Aβ and tau prions from DS brain homogenates and measured the number of prions using cellular bioassays. In brain extracts from 28 deceased donors with DS, ranging in age from 19 to 65 y, we found nearly all DS brains had readily measurable levels of Aβ and tau prions. In a cross-sectional analysis of DS donor age at death, we found that the levels of Aβ and tau prions increased with age. In contrast to DS brains, the levels of Aβ and tau prions in the brains of 37 fAD and sAD donors decreased as a function of age at death. Whether DS is an ideal model for assessing the efficacy of putative AD therapeutics remains to be determined.</div><div><br /></div><div><a href="https://www.pnas.org/doi/epdf/10.1073/pnas.2212954119" rel="nofollow" style="color: #196ad4;" target="_blank">https://www.pnas.org/doi/epdf/10.1073/pnas.2212954119</a><br /></div><div><br /></div><div><br /></div><div><br /></div></div></div>Terry S. Singeltary Sr.http://www.blogger.com/profile/06986622967539963260noreply@blogger.com0tag:blogger.com,1999:blog-6491423064023155264.post-75040643900187996652017-12-12T10:56:00.001-06:002017-12-12T10:56:18.276-06:00Neuropathology of iatrogenic Creutzfeldt–Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology<span style="font-family: arial, helvetica;"><span style="font-size: 10pt;">Neuropathology of iatrogenic Creutzfeldt–Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology</span></span><br /><br />
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Neuropathology of iatrogenic Creutzfeldt–Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology </div>
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Charles Duyckaerts Véronique Sazdovitch Kunie Ando Danielle Seilhean Nicolas PrivatZehra Yilmaz Laurène Peckeu Elodie Amar Emmanuel Comoy Aleksandra Maceski Sylvain Lehmann Jean-Pierre Brion Jean-Philippe Brandel Stéphane Haïk</div>
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First Online: 22 November 2017</div>
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Abeta deposits and tau pathology were investigated in 24 French patients that died from iatrogenic Creutzfeldt–Jakob disease after exposure to cadaver-derived human growth hormone (c-hGH) in the 1980s. Abeta deposits were found only in one case that had experienced one of the longest incubation periods. Three cases had also intracellular tau accumulation. The analysis of 24 batches of c-hGH, produced between 1974 and 1988, demonstrated for the first time the presence of Abeta and tau contaminants in c-hGH (in 17 and 6 batches, respectively). The incubation of prion disease was shorter in the French patients than the incubation times reported in two previously published British series. We interpreted the low incidence of Abeta in this French series as a consequence of the shorter incubation period observed in France, as compared to that observed in the United Kingdom. This concept suggested that a mean incubation period for the development of detectable Abeta deposits would be longer than 18 years after the first exposure. Moreover, we hypothesized that tau pathology might also be transmissible in humans.</div>
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Keywords Creutzfeldt–Jakob disease Abeta pathology Tau pathology Alzheimer’s disease Transmission Prions Growth hormone </div>
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<a href="https://link.springer.com/article/10.1007%2Fs00401-017-1791-x" rel="noopener noreferrer" style="color: #0096ef; text-decoration-line: none;" target="_blank">https://link.springer.com/article/10.1007%2Fs00401-017-1791-x</a></div>
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***Moreover, we hypothesized that tau pathology might also be transmissible in humans.</div>
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Molecular Psychiatry , (31 October 2017) | doi:10.1038/mp.2017.204</div>
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Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies</div>
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X-L Bu, Y Xiang, W-S Jin, J Wang, L-L Shen, Z-L Huang, K Zhang, Y-H Liu, F Zeng, J-H Liu, H-L Sun, Z-Q Zhuang, S-H Chen, X-Q Yao, B Giunta, Y-C Shan, J Tan, X-W Chen, Z-F Dong, H-D Zhou, X-F Zhou, W Song and Y-J Wang</div>
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The amyloid-β protein (Aβ) protein plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). It is believed that Aβ deposited in the brain originates from the brain tissue itself. However, Aβ is generated in both brain and peripheral tissues. Whether circulating Aβ contributes to brain AD-type pathologies remains largely unknown. In this study, using a model of parabiosis between APPswe/PS1dE9 transgenic AD mice and their wild-type littermates, we observed that the human Aβ originated from transgenic AD model mice entered the circulation and accumulated in the brains of wild-type mice, and formed cerebral amyloid angiopathy and Aβ plaques after a 12-month period of parabiosis. AD-type pathologies related to the Aβ accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice. More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice. To the best of our knowledge, our study is the first to reveal that blood-derived Aβ can enter the brain, form the Aβ-related pathologies and induce functional deficits of neurons. Our study provides novel insight into AD pathogenesis and provides evidence that supports the development of therapies for AD by targeting Aβ metabolism in both the brain and the periphery.</div>
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<a href="https://www.nature.com/mp/journal/vaop/ncurrent/full/mp2017204a.html" rel="noopener noreferrer" style="color: blue;" target="_blank">https://www.nature.com/mp/journal/vaop/ncurrent/full/mp2017204a.html</a></div>
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Alzheimer’s disease, iatrogenic, and Transmissible Spongiform Encephalopathy TSE Prion disease, that is the question ??? </div>
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>>> The only tenable public line will be that "more research is required’’ <<< </div>
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>>> possibility on a transmissible prion remains open<<< </div>
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O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ?</div>
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[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication. There are also results to be made available shortly (1) concerning a farmer with CJD who had BSE animals, (2) on the possible transmissibility of Alzheimer’s and (3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]</div>
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<a href="https://web.archive.org/web/20170126060344/http://collections.europarchive.org/tna/20080102232842/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf" rel="noopener noreferrer" style="color: blue;" target="_blank">https://web.archive.org/web/20170126060344/http://collections.europarchive.org/tna/20080102232842/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf</a></div>
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<span style="font-size: 10pt;">snip...see full Singeltary Nature comment here; </span></div>
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<a href="http://www.nature.com/nature/journal/v525/n7568/full/nature15369.html#/comments" rel="noopener noreferrer" style="color: blue;" target="_blank">http://www.nature.com/nature/journal/v525/n7568/full/nature15369.html#/comments</a></div>
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<span style="font-size: 10pt;">see Singeltary comments to Plos ; </span></div>
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Subject: 1992 IN CONFIDENCE TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES POSSIBILITY ON A TRANSMISSIBLE PRION REMAINS OPEN </div>
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BSE101/1 0136 </div>
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IN CONFIDENCE </div>
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CMO </div>
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From: . Dr J S Metiers DCMO 4 </div>
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November 1992 </div>
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TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES </div>
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1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognised the public sensitivity of these findings and intend to report them in their proper context. 'This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify. </div>
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2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed". As the report emphasises the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible. what are the implications for public health? </div>
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3. The route 'of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. </div>
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However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed. 1 </div>
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BSE101/1 0137 4. </div>
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The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. </div>
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The only tenable public line will be that "more research is required’’ before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical. </div>
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J S METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832 llllYc!eS 2 92/11.4/1.2 </div>
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<a href="https://web.archive.org/web/20160320084827/http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf" rel="noopener noreferrer" style="color: blue;" target="_blank">https://web.archive.org/web/20160320084827/http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf</a></div>
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>>> The only tenable public line will be that "more research is required’’ <<< </div>
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>>> possibility on a transmissible prion remains open<<< </div>
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O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ? </div>
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Re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy </div>
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Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015) </div>
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snip...see full Singeltary Nature comment here; </div>
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Alzheimer's disease</div>
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let's not forget the elephant in the room. curing Alzheimer's would be a great and wonderful thing, but for starters, why not start with the obvious, lets prove the cause or causes, and then start to stop that. think iatrogenic, friendly fire, or the pass it forward mode of transmission. think medical, surgical, dental, tissue, blood, related transmission. think transmissible spongiform encephalopathy aka tse prion disease aka mad cow type disease... </div>
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<span style="font-size: x-small;">Commentary: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy</span></div>
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<span style="font-size: x-small;"><a href="http://journals.plos.org/plosone/article/comment?id=info:doi/10.1371/annotation/933cc83a-a384-45c3-b3b2-336882c30f9d" rel="noopener noreferrer" style="color: blue;" target="_blank">http://journals.plos.org/plosone/article/comment?id=info:doi/10.1371/annotation/933cc83a-a384-45c3-b3b2-336882c30f9d</a></span></div>
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Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease </div>
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*** Singeltary comment PLoS *** </div>
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Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ? </div>
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Posted by flounder on 05 Nov 2014 at 21:27 GMT </div>
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Ann N Y Acad Sci. 1982;396:131-43. </div>
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Alzheimer's disease and transmissible virus dementia (Creutzfeldt-Jakob disease). </div>
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Brown P, Salazar AM, Gibbs CJ Jr, Gajdusek DC. </div>
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Abstract </div>
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Ample justification exists on clinical, pathologic, and biologic grounds for considering a similar pathogenesis for AD and the spongiform virus encephalopathies. However, the crux of the comparison rests squarely on results of attempts to transmit AD to experimental animals, and these results have not as yet validated a common etiology. Investigations of the biologic similarities between AD and the spongiform virus encephalopathies proceed in several laboratories, and our own observation of inoculated animals will be continued in the hope that incubation periods for AD may be even longer than those of CJD. </div>
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<a href="http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.1982.tb26849.x/abstract" rel="noopener noreferrer" style="color: blue;" target="_blank">http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.1982.tb26849.x/abstract </a></div>
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Sunday, November 22, 2015 </div>
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*** Effect of heating on the stability of amyloid A (AA) fibrils and the intra- and cross-species transmission of AA amyloidosis </div>
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Abstract </div>
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Amyloid A (AA) amyloidosis is a protein misfolding disease characterized by extracellular deposition of AA fibrils. AA fibrils are found in several tissues from food animals with AA amyloidosis. For hygienic purposes, heating is widely used to inactivate microbes in food, but it is uncertain whether heating is sufficient to inactivate AA fibrils and prevent intra- or cross-species transmission. We examined the effect of heating (at 60 °C or 100 °C) and autoclaving (at 121 °C or 135 °C) on murine and bovine AA fibrils using Western blot analysis, transmission electron microscopy (TEM), and mouse model transmission experiments. TEM revealed that a mixture of AA fibrils and amorphous aggregates appeared after heating at 100 °C, whereas autoclaving at 135 °C produced large amorphous aggregates. AA fibrils retained antigen specificity in Western blot analysis when heated at 100 °C or autoclaved at 121 °C, but not when autoclaved at 135 °C. Transmissible pathogenicity of murine and bovine AA fibrils subjected to heating (at 60 °C or 100 °C) was significantly stimulated and resulted in amyloid deposition in mice. Autoclaving of murine AA fibrils at 121 °C or 135 °C significantly decreased amyloid deposition. Moreover, amyloid deposition in mice injected with murine AA fibrils was more severe than that in mice injected with bovine AA fibrils. Bovine AA fibrils autoclaved at 121 °C or 135 °C did not induce amyloid deposition in mice. These results suggest that AA fibrils are relatively heat stable and that similar to prions, autoclaving at 135 °C is required to destroy the pathogenicity of AA fibrils. These findings may contribute to the prevention of AA fibril transmission through food materials to different animals and especially to humans. </div>
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Purchase options Price * Issue Purchase USD 511.00 Article Purchase USD 54.00 </div>
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<a href="http://www.tandfonline.com/doi/abs/10.3109/13506129.2015.1095735?journalCode=iamy20" rel="noopener noreferrer" style="color: blue;" target="_blank">http://www.tandfonline.com/doi/abs/10.3109/13506129.2015.1095735?journalCode=iamy20</a> </div>
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<a href="http://betaamyloidcjd.blogspot.com/2015/11/effect-of-heating-on-stability-of.html" rel="noopener noreferrer" style="color: blue;" target="_blank">http://betaamyloidcjd.blogspot.com/2015/11/effect-of-heating-on-stability-of.html</a> </div>
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*** Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery *** </div>
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Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC. </div>
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Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them. </div>
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<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8006664&dopt=Abstract" rel="noopener noreferrer" style="color: blue;" target="_blank">http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8006664&dopt=Abstract </a></div>
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Diagnosis and Reporting of Creutzfeldt-Jakob Disease </div>
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Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA Diagnosis and Reporting of Creutzfeldt-Jakob Disease </div>
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To the Editor: </div>
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In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally. </div>
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Terry S. Singeltary, Sr Bacliff, Tex </div>
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1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. </div>
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<a href="http://jama.jamanetwork.com/article.aspx?articleid=1031186" rel="noopener noreferrer" style="color: blue;" target="_blank">http://jama.jamanetwork.com/article.aspx?articleid=1031186 </a></div>
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WEDNESDAY, NOVEMBER 1, 2017 </div>
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Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies</div>
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<a href="http://betaamyloidcjd.blogspot.com/2017/11/blood-derived-amyloid-protein-induces.html" rel="noopener noreferrer" style="color: blue;" target="_blank">http://betaamyloidcjd.blogspot.com/2017/11/blood-derived-amyloid-protein-induces.html</a></div>
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<a href="http://tauopathies.blogspot.com/" style="color: #0096ef; text-decoration-line: none;">http://tauopathies.blogspot.com/</a></div>
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<a href="http://alpha-synuclein.blogspot.com/" style="color: #0096ef; text-decoration-line: none;">http://alpha-synuclein.blogspot.com/</a></div>
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<a href="http://synucleinopathies.blogspot.com/" style="color: #0096ef; text-decoration-line: none;">http://synucleinopathies.blogspot.com/</a></div>
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<a href="http://synucleinopathy.blogspot.com/" style="color: #0096ef; text-decoration-line: none;">http://synucleinopathy.blogspot.com/</a> (no post yet...tss)</div>
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<a href="http://creutzfeldt-jakob-disease.blogspot.com/" style="color: #0096ef; text-decoration-line: none;">http://creutzfeldt-jakob-disease.blogspot.com/</a></div>
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<a href="http://cjdtexas.blogspot.com/" style="color: #0096ef; text-decoration-line: none;">http://cjdtexas.blogspot.com/</a></div>
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<a href="http://vcjd.blogspot.com/" style="color: #0096ef; text-decoration-line: none;">http://vcjd.blogspot.com/</a></div>
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<a href="http://vcjdblood.blogspot.com/" style="color: #0096ef; text-decoration-line: none;">http://vcjdblood.blogspot.com/</a></div>
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<a href="http://vcjdtransfusion.blogspot.com/" style="color: #0096ef; text-decoration-line: none;">http://vcjdtransfusion.blogspot.com/</a></div>
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<a href="http://transmissiblespongiformencephalopathy.blogspot.com/" style="color: #0096ef; text-decoration-line: none;">http://transmissiblespongiformencephalopathy.blogspot.com/</a></div>
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<a href="http://chronic-wasting-disease.blogspot.com/" style="color: #0096ef; text-decoration-line: none;">http://chronic-wasting-disease.blogspot.com/</a></div>
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<a href="http://bovineprp.blogspot.com/" style="color: #0096ef; text-decoration-line: none;">http://bovineprp.blogspot.com/</a></div>
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<a href="http://nor-98.blogspot.com/" style="color: #0096ef; text-decoration-line: none;">http://nor-98.blogspot.com/</a></div>
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<a href="http://prionunitusaupdate.blogspot.com/" style="color: #0096ef; text-decoration-line: none;">http://prionunitusaupdate.blogspot.com/</a></div>
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FOR OVER 4 YEARS, USDA et al decided they should supply the National School Lunch Program with the most high risk cattle for mad cow disease i.e. dead stock downer cows. i'm not making this stuff up folks. they hid what at the time was the largest beef recall ever, they hid the cause of the recall, and listed it as 'animal abuse'. yes, yes, you read that right. they largest beef recall at the time in history, and the reason was animal abuse, NOT THE FACT THE DEAD STOCK DOWN COWS ARE THE MOST HIGH RISK FOR TSE PRION...TSS</div>
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<span style="font-family: arial, helvetica;">Saturday, September 21, 2013</span></div>
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<span style="font-family: arial, helvetica;">Westland/Hallmark: 2008 Beef Recall A Case Study by The Food Industry Center January 2010 THE FLIM-FLAM REPORT</span></div>
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<a href="http://downercattle.blogspot.com/2013/09/westlandhallmark-2008-beef-recall-case.html" style="color: #0096ef; text-decoration-line: none;">http://downercattle.blogspot.com/2013/09/westlandhallmark-2008-beef-recall-case.html</a></div>
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<span style="font-family: arial, helvetica;">DID YOUR CHILD CONSUME SOME OF THESE DEAD STOCK DOWNER COWS, THE MOST HIGH RISK FOR MAD COW DISEASE ???</span></div>
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<span style="font-family: arial, helvetica;">this recall was not for the welfare of the animals. ...tss</span></div>
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<span style="font-family: arial, helvetica;">you can check and see here ;</span></div>
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<span style="font-family: arial, helvetica;">(link now dead, does not work...tss)</span></div>
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<a href="http://www.fns.usda.gov/fns/safety/pdf/Hallmark-Westland_byState.pdf" style="color: #0096ef; text-decoration-line: none;">http://www.fns.usda.gov/fns/safety/pdf/Hallmark-Westland_byState.pdf</a></div>
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<span style="font-family: arial, helvetica;">try this link ;</span></div>
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<a href="http://downercattle.blogspot.com/2013/09/school-food-authorities-affected-by.html" style="color: #0096ef; text-decoration-line: none;">http://downercattle.blogspot.com/2013/09/school-food-authorities-affected-by.html</a></div>
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<a href="http://downercattle.blogspot.com/" style="color: #0096ef; text-decoration-line: none;">http://downercattle.blogspot.com/</a></div>
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<a href="http://cjdquestionnaire.blogspot.com/2007/" style="color: #0096ef; text-decoration-line: none;">http://cjdquestionnaire.blogspot.com/2007/</a></div>
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Terry S. Singeltary Sr.</div>
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Terry S. Singeltary Sr.http://www.blogger.com/profile/06986622967539963260noreply@blogger.com0tag:blogger.com,1999:blog-6491423064023155264.post-7945799348441562482017-07-09T12:51:00.001-05:002017-07-12T13:32:36.714-05:00Scientists uncover the structure of tau filaments from Alzheimer's diseaseScientists uncover the structure of tau filaments from Alzheimer's disease<br />
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5 Jul 2017<br />
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Researchers at the MRC Laboratory of Molecular Biology (LMB) have, for the first time, revealed the atomic structures of one of the two types of the abnormal filaments which lead to Alzheimer's disease. Understanding the structures of these filaments will be key in developing drugs to prevent their formation.<br />
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The researchers, whose study is published today in Nature, believe the structures they have uncovered could also suggest how tau protein may form different filaments in other neurodegenerative diseases.<br />
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Alzheimer’s, the most common neurodegenerative disease, is characterised by the existence of two types of abnormal ‘amyloid’ forms of protein which form lesions in the brain. Tau forms filaments inside nerve cells and amyloid-beta forms filaments outside cells. Tau lesions appear to have a stronger correlation to the loss of cognitive ability in patients with the disease.<br />
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Almost thirty years ago, scientists at the LMB (including Michel Goedert, one of the senior authors on this paper) identified tau protein as an integral component of the lesions found in Alzheimer’s and a range of other neurodegenerative diseases. But, until now, scientists have been unable to identify the atomic structure of the filaments.<br />
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The researchers extracted tau filaments from the brain of a patient who had died with Alzheimer's disease. The filaments were then imaged using cryo-electron microscopy (cryo-EM). Senior author Sjors Scheres and colleagues developed new software in order to calculate the structure of the filaments in sufficient detail to deduce the arrangement of the atoms inside them.<br />
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Sjors Scheres said: “It’s very exciting that we were able to use this new technique to visualise filaments from a diseased brain as previous work depended on artificial samples assembled in the laboratory. Amyloid structures can form in many different ways, so it has been unclear how close these lab versions resembled those in human disease.<br />
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“Knowing which parts of tau are important for filament formation is relevant for the development of drugs. For example, many pharmaceutical companies are currently using different parts of tau in tests to measure the effect of different drugs on filament formation; this new knowledge should significantly increase the accuracy of such tests."<br />
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Fellow senior author Michel Goedert said: “We have known for almost three decades that the abnormal assembly of tau protein into filaments is a defining characteristic of Alzheimer's disease. In 1998, the dysfunction of tau protein was shown to be sufficient for neurodegeneration and dementia. In 2009, the prion-like properties of assembled tau were identified. These properties allow the abnormal form to convert previously normal forms.<br />
<br />
“Until now the high-resolution structures of tau or any other disease-causing filaments from human brain tissue have remained unknown. This new work will help to develop better compounds for diagnosing and treating Alzheimer's and other diseases which involve defective tau.”<br />
<br />
Dr Rob Buckle, chief science officer at the MRC, which funded the research, said: “This ground-breaking work is a major contribution to our understanding of Alzheimer's disease. Nearly thirty years ago scientists at the LMB were the first to discover that tau protein plays a key role in the disease. Knowing the basic structure of these filaments in diseased tissue is vital for the development of drugs to combat their formation.<br />
<br />
“This research opens up new possibilities to study a range of other diseases where the accumulation of abnormal protein filaments plays a role, including Parkinson’s disease, motor neuron disease and prion diseases.”<br />
<br />
The work was funded by the MRC, the European Union, US National Institutes of Health and the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine.<br />
<br />
<a href="https://www.mrc.ac.uk/news/browse/scientists-uncover-the-structure-of-tau-filaments-from-alzheimer-s-disease/"> https://www.mrc.ac.uk/news/browse/scientists-uncover-the-structure-of-tau-filaments-from-alzheimer-s-disease/</a><br />
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Cryo-EM structures of tau filaments from Alzheimer’s disease<br />
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Anthony W. P. Fitzpatrick, Benjamin Falcon, Shaoda He, Alexey G. Murzin, Garib Murshudov, Holly J. Garringer, R. Anthony Crowther, Bernardino Ghetti, Michel Goedert & Sjors H. W. Scheres<br />
<br />
AffiliationsContributionsCorresponding authors Nature (2017) doi:10.1038/nature23002 Received 24 February 2017 Accepted 05 June 2017 Published online 05 July 2017 Article tools<br />
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Abstract<br />
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Abstract• Accession codes• References• Author information• Extended data figures and tables<br />
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Alzheimer’s disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4–3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer’s disease. Filament cores are made of two identical protofilaments comprising residues 306–378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.<br />
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At a glance<br />
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snip...see images and more ;<br />
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<a href="https://www.nature.com/nature/journal/vaop/ncurrent/full/nature23002.html?sf95445996=1#acknowledgments">https://www.nature.com/nature/journal/vaop/ncurrent/full/nature23002.html?sf95445996=1#acknowledgments</a><br />
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Neurodegeneration: Taming tangled tau<br />
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David S. Eisenberg & Michael R. Sawaya Affiliations Corresponding authors Nature (2017) doi:10.1038/nature23094<br />
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Published online 05 July 2017<br />
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Article tools Citation Rights & permissions Article metrics<br />
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The protein tau forms abnormal filamentous aggregates called tangles in the brains of people with neurodegeneration. Structures of two such filaments offer pathways to a deeper understanding of Alzheimer's disease.<br />
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<a href="https://www.nature.com/nature/journal/vaop/ncurrent/full/nature23094.html">https://www.nature.com/nature/journal/vaop/ncurrent/full/nature23094.html</a><br />
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=====PRION 2017 CONFERENCE ABSTRACTS=====<br />
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P154 Development of an in vitro amplification assay for misfolded proteins in for misfolded proteins in Alzheimer’s diseases (AD) and Parkinson’s disease (PD)<br />
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Ms Susana Margarida Silva Correia1<br />
1National Reference Center For Tse, Department Of Neurology, Georg-august University , Göttingen, Germany<br />
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A characteristic feature of major neurodegenerative diseases leading to dementia is the progressive accumulation of protein aggregates in the brain in a self-propagation-manner with a regional pattern specific to each disease. The concept of protein misfolding was initially thought to play a crucial role mainly in prion diseases, recent studies identified similar characteristics for amyloid beta, tau and alpha synuclein in various models. The term “prion-like“ protein propagation is now widely used to address the mechanisms which might play a role in amyloidopathies or tauopathies such as Alzheimer’s disease (AD) and alpha synucleinopathies, such as Parkinson’s disease (PD) or Lewy body dementia (LBD).<br />
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We established the RT-QuIC for the amplification of prion protein scrapie (PrPSc) in human brain tissue and cerebrospinal fluid (CSF) of CJD-patients (Schmitz M et al, 2016). The technique bears a huge diagnostic and analytical potential also for other misfolded proteins, which are showing a prion-like mechanism of protein misfolding.<br />
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The aim of the study is the implementation of the amyloid beta and alpha synuclein QuIC in diagnostic of neurodegenerative diseases. In particular, we aim to improve the diagnostic of AD, PD and LBD. The implementation of the amyloid beta and alpha synuclein QuIC in human disease diagnostic requires the analysis of a huge cohort of patients (available from our biobank) consisting of healthy controls, patients with alternative diagnosis as well as of patients with AD and PD.<br />
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The aim of the study is to develop the RT-QuIC to create a novel diagnostic-tests for other neurodegenerative diseases such as AD and PD. In a first step, we plan to produce recombinant amyloid beta and alpha synuclein and to test systematically different substrates in our QuIC-amplification assay. After validation of the most suitable substrates, we will applicate the RT-QuIC for the detection of amyloid beta and alpha synuclein aggregates in CSF from AD- and PD-patients.<br />
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=====<br />
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P188 Misfolded PrP is not always associated with formation of p-tau<br />
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Dr Debbie Brown1, Mr Declan King1, Dr Rona Barron1, Professor Pedro Piccardo1<br />
1Roslin Institute, Edinburgh, United Kingdom<br />
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The conversion of cellular prion protein into a misfolded isoform is central to the development of prion diseases. Amyloid beta (Aβ) and hyperphosphorylated tau (p-tau) participate in the pathogenesis of Alzheimer´s disease (AD). Additionally several prion diseases in humans accumulate p-tau in the brain and therefore we hypothesise that proteins that participate in the pathogenesis of one disease may play a role in other disorders to establish complex proteinopathies, a mechanism that could explain the phenotypic variability observed in prion diseases. To explore this possibility we analysed p-tau accumulation in mouse models with varying degrees of PrP deposits in the brain. We used animals inoculated with :- mouse-adapted prion agents, typical and atypical bovine spongiform encephalopathy agents along with mice inoculated with wild-type (Wt) /mutant (101L) recombinant PrP fibrils and mice overexpressing 101L PrP. We observed that p-tau is consistently present in animals with prion infectivity (i.e. models that transmit disease upon serial passage). However, p-tau is not observed in non-prion mice inoculated with recombinant PrP fibrils or mice overexpressing PrP, both of which form large amyloid plaques in the absence of disease. The data suggest that p-tau is not necessarily associated with deposition of misfolded PrP, but that the interaction between the prion agent and host regulates the formation of p-tau and may contribute to the heterogeneous phenotype of prion diseases.<br />
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=====<br />
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P17 Induction of transmissible tau pathology by traumatic brain Injury<br />
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Dr Elisa R Zanier1, Ilaria Bertani1, Dr Maria Antonietta Chiaravalloti1, Dr Eliana Sammali1, Dr Francesca Pischiutta1, Dr Gloria Vegliante1, Dr Fabrizio Ortolano2, Dr Nino Stocchetti2,3, Dr Maria-Grazia De Simoni1, Dr Roberto Chiesa1<br />
1Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy, 2Università degli Studi di Milano, Milano, Italy, 3Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano, Milano, Italy<br />
<br />
Aims: The aim of this study was to test whether traumatic brain injury (TBI), a risk factor for Alzheimer’s disease and chronic traumatic encephalopathy, induces a tau pathology that spreads in the brain in a prion-like manner, causing functional and histopathological abnormalities.<br />
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Methods: C57BL/6J mice were subjected to focal TBI by single controlled cortical impact, and the presence of pathological tau was investigated by immunohistochemistry and Western blot using antibodies specific for different phosphorylated tau isoforms. The emergence of self-propagating tau isoform was investigated by inoculating 10% brain homogenates from TBI mice and humans into the brain of naïve C57BL/6J mice.<br />
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Results: Hyperphosphorylated tau was detected in the injured brain hemisphere at 3 months post-TBI, and in the ipsi and contralateral hemispheres at 12 months, indicating progressive spreading of tauopathy. Mice inoculated with TBI brain homogenates developed memory deficits detectable by the novel object recognition task at 4, 8 and 12 months after inoculation. Immunohistochemistry at 12 months post-inoculation showed hyperphosphorylated tau in the injected area and remote brain regions.<br />
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Conclusions: Results establish that a single focal TBI induces a tau pathology in wild-type mice that progressively spreads from the site of injury to other brain regions. They also show the emergence of self-propagating tau isoforms in the brains of TBI mice and humans, which can be transmitted to wild-type mice like bona fide prions, inducing memory dysfunction. These data suggest that inhibiting propagation of tau may become a treatment strategy in TBI.<br />
<br />
=====WOW AMAZING...TSS=====<br />
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WEDNESDAY, JUNE 14, 2017<br />
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Amyloid-β accumulation in human growth hormone related iatrogenic CJD patients in the UK<br />
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<a href="http://betaamyloidcjd.blogspot.com/2017/06/amyloid-accumulation-in-human-growth.html">http://betaamyloidcjd.blogspot.com/2017/06/amyloid-accumulation-in-human-growth.html</a><br />
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Saturday, June 17, 2017<br />
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PRION 2017 P115 α- Synuclein prions from MSA patients exhibit similar transmission properties as PrPSc prions<br />
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<a href="http://msaprion.blogspot.com/2017/06/prion-2017-p115-synuclein-prions-from.html">http://msaprion.blogspot.com/2017/06/prion-2017-p115-synuclein-prions-from.html</a><br />
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Thursday, July 6, 2017<br />
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PRION 2017 CONFERENCE ABSTRACTS HUMAN TSE PRION DISEASE<br />
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<a href="http://prionprp.blogspot.com/2017/07/prion-2017-conference-abstracts-human.html">http://prionprp.blogspot.com/2017/07/prion-2017-conference-abstracts-human.html</a><br />
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TUESDAY, JUNE 20, 2017<br />
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Prion 2017 Conference Transmissible prions in the skin of Creutzfeldt-Jakob disease patients<br />
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<a href="http://creutzfeldt-jakob-disease.blogspot.com/2017/06/prion-2017-conference-transmissible.html">http://creutzfeldt-jakob-disease.blogspot.com/2017/06/prion-2017-conference-transmissible.html</a><br />
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WEDNESDAY, MAY 03, 2017<br />
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*** First evidence of intracranial and peroral transmission of Chronic Wasting Disease (CWD) into Cynomolgus macaques<br />
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<a href="http://chronic-wasting-disease.blogspot.com/2017/05/first-evidence-of-intracranial-and.html"> http://chronic-wasting-disease.blogspot.com/2017/05/first-evidence-of-intracranial-and.html</a><br />
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FRIDAY, JUNE 16, 2017<br />
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PRION 2017 P55 Susceptibility of human prion protein to in vitro conversion by chronic wasting disease prions<br />
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<a href="http://chronic-wasting-disease.blogspot.com/2017/06/p55-susceptibility-of-human-prion.html">http://chronic-wasting-disease.blogspot.com/2017/06/p55-susceptibility-of-human-prion.html</a><br />
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MONDAY, JUNE 19, 2017<br />
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PRION 2017 P20 Descriptive epidemiology of human prion diseases in Japan: a prospective 16-year surveillance study<br />
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Japan Prion Disease Increasing Annually to 2.3 patients per 1 million populations in 2014<br />
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<a href="http://creutzfeldt-jakob-disease.blogspot.com/2017/06/prion-2017-p20-descriptive-epidemiology.html">http://creutzfeldt-jakob-disease.blogspot.com/2017/06/prion-2017-p20-descriptive-epidemiology.html</a><br />
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TUESDAY, JUNE 13, 2017<br />
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PRION 2017 CONFERENCE ABSTRACT Chronic Wasting Disease in European moose is associated with PrPSc features different from North American CWD<br />
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<a href="http://chronic-wasting-disease.blogspot.com/2017/06/prion-2017-conference-abstract-chronic.html">http://chronic-wasting-disease.blogspot.com/2017/06/prion-2017-conference-abstract-chronic.html</a><br />
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SATURDAY, JUNE 10, 2017<br />
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Chronic Wasting Disease CWD TSE Prion to Humans, who makes that final call, when, or, has it already happened?<br />
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<a href="http://chronic-wasting-disease.blogspot.com/2017/06/chronic-wasting-disease-cwd-tse-prion_10.html">http://chronic-wasting-disease.blogspot.com/2017/06/chronic-wasting-disease-cwd-tse-prion_10.html</a><br />
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MONDAY, JUNE 19, 2017</div>
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PRION 2017 CONFERENCE ABSTRACT P61 vCJD strain properties in a Spanish mother and son replicate as those of a young UK case</div>
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<a href="http://vcjd.blogspot.com/2017/06/prion-2017-conference-abstract-p61-vcjd.html" style="color: blue; cursor: pointer;" target="_blank">http://vcjd.blogspot.com/2017/06/prion-2017-conference-abstract-p61-vcjd.html</a></div>
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TUESDAY, JULY 04, 2017</div>
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PRION 2017 CONFERENCE ABSTRACTS ON CHRONIC WASTING DISEASE CWD TSE PRION</div>
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<a href="http://chronic-wasting-disease.blogspot.com/2017/07/prion-2017-conference-abstracts-on.html" style="color: blue; cursor: pointer;" target="_blank">http://chronic-wasting-disease.blogspot.com/2017/07/prion-2017-conference-abstracts-on.html</a></div>
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Subject: PRION 2017 CONFERENCE DECIPHERING NEURODEGENERATIVE DISORDERS VIDEO</div>
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PRION 2017 CONFERENCE DECIPHERING NEURODEGENERATIVE DISORDERS</div>
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PRION 2017 CONFERENCE VIDEO</div>
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<a href="http://prion2017.org/programme/" style="color: blue; cursor: pointer;" target="_blank">http://prion2017.org/programme/</a></div>
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Thursday, June 29, 2017</div>
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PRION 2017 CONFERENCE DECIPHERING NEURODEGENERATIVE DISORDERS VIDEO</div>
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<a href="http://prionprp.blogspot.com/2017/06/prion-2017-conference-deciphering.html" style="color: blue; cursor: pointer;" target="_blank">http://prionprp.blogspot.com/2017/06/prion-2017-conference-deciphering.html</a></div>
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Wednesday, May 24, 2017</div>
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PRION2017 CONFERENCE VIDEO UPDATE 23 – 26 May 2017 Edinburgh UPDATE 1</div>
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Subject: PRION2017 CONFERENCE VIDEO UPDATE 23 – 26 May 2017 Edinburgh</div>
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*see archives of previous Prion Conferences, the ones that are still available, scroll down towards bottom in this link.</div>
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<a href="http://prionprp.blogspot.com/2017/05/prion2017-conference-video-update-23-26.html" style="color: blue; cursor: pointer;" target="_blank">http://prionprp.blogspot.com/2017/05/prion2017-conference-video-update-23-26.html</a></div>
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<a href="http://prion2017.org/wp-content/uploads/2017/05/PRION-2017-A-Z-of-Abstracts-by-Presenter_2-2.pdf" style="color: blue; cursor: pointer;" target="_blank">http://prion2017.org/wp-content/uploads/2017/05/PRION-2017-A-Z-of-Abstracts-by-Presenter_2-2.pdf</a></div>
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THURSDAY, JUNE 22, 2017</div>
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National Prion Disease Pathology Surveillance Center Cases Examined(1) (May 18, 2017)</div>
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Terry S. Singeltary Sr.http://www.blogger.com/profile/06986622967539963260noreply@blogger.com0tag:blogger.com,1999:blog-6491423064023155264.post-76503626623779005442017-06-07T12:35:00.001-05:002017-06-07T12:35:24.360-05:00Characterization of tau prion seeding activity and strains from formaldehyde-fixed tissue<div class="FulltextWrapper" style="background-color: white; box-sizing: border-box; color: #333333; font-family: "Open Sans";">
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Characterization of tau prion seeding activity and strains from formaldehyde-fixed tissue</h1>
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<span class="ArticleCitation" style="border-right: 1px solid rgb(220, 220, 220); box-sizing: border-box; display: block; margin-right: 8px; padding-right: 8px;"><span class="JournalTitle" style="box-sizing: border-box; display: inline-block; font-style: italic; margin-right: 8px;" xmlns="http://www.w3.org/1999/xhtml">Acta Neuropathologica Communications</span><span class="JournalSubTitle" style="box-sizing: border-box; display: inline-block; margin-right: 8px;" xmlns="http://www.w3.org/1999/xhtml">Neuroscience of Disease</span><span class="ArticleCitation_Year" style="box-sizing: border-box; display: inline-block; margin-right: 8px;">2017</span><span class="ArticleCitation_Volume" style="box-sizing: border-box; display: inline-block; margin-right: 0px;"><span style="-webkit-font-smoothing: antialiased; box-sizing: border-box; font-weight: 700;">5</span>:41</span></span></div>
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<span style="-webkit-font-smoothing: antialiased; box-sizing: border-box; font-weight: 700;">DOI: </span>10.1186/s40478-017-0442-8</div>
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© The Author(s). 2017</div>
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<span style="-webkit-font-smoothing: antialiased; box-sizing: border-box; font-weight: 700;">Received: </span>11 May 2017</div>
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<span style="-webkit-font-smoothing: antialiased; box-sizing: border-box; font-weight: 700;">Accepted: </span>11 May 2017</div>
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<span style="-webkit-font-smoothing: antialiased; box-sizing: border-box; font-weight: 700;">Published: </span>7 June 2017</div>
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<section class="Abstract" id="Abs1" lang="en" style="box-sizing: border-box; margin-top: 36px;" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:meta="http://www.springer.com/app/meta" xmlns=""><h2 class="Heading js-ToggleCollapseSection" style="-webkit-font-smoothing: antialiased; box-sizing: border-box; color: #333333; font-family: Lora; font-size: 1.625rem; font-weight: 400; line-height: 1.4; margin-bottom: 24px; margin-top: 0px;">
Abstract</h2>
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Tauopathies such as Alzheimer’s disease (AD) feature progressive intraneuronal deposition of aggregated tau protein. The cause is unknown, but in experimental systems trans-cellular propagation of tau pathology resembles prion pathogenesis. Tau aggregate inoculation into mice produces transmissible pathology, and tau forms distinct strains, i.e. conformers that faithfully replicate and create predictable patterns of pathology in vivo. The prion model predicts that tau seed formation will anticipate neurofibrillary tau pathology. To test this idea requires simultaneous assessment of seed titer and immunohistochemistry (IHC) of brain tissue, but it is unknown whether tau seed titer can be determined in formaldehyde-fixed tissue. We have previously created a cellular biosensor system that uses flow cytometry to quantify induced tau aggregation and thus determine seed titer. In unfixed tissue from PS19 tauopathy mice that express 1 N,4R tau (P301S), we have measured tau seeding activity that precedes the first observable histopathology by many months. Additionally, in fresh frozen tissue from human AD subjects at early to mid-neurofibrillary tangle stages (NFT I-IV), we have observed tau seeding activity in cortical regions predicted to lack neurofibrillary pathology. However, we could not directly compare the same regions by IHC and seeding activity in either case. We now describe a protocol to extract and measure tau seeding activity from small volumes (.04 mm<span style="box-sizing: border-box; font-size: 12px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">3</span>) of formaldehyde-fixed tissue immediately adjacent to that used for IHC. We validated this method with the PS19 transgenic mouse model, and easily observed seeding well before the development of phospho-tau pathology. We also accurately isolated two tau strains, DS9 and DS10, from fixed brain tissues in mice. Finally, we have observed robust seeding activity in fixed AD brain, but not controls. The successful coupling of classical IHC with seeding and strain detection should enable detailed study of banked brain tissue in AD and other tauopathies.</div>
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<span style="font-family: Arial, Helvetica, sans-serif;">snip...</span></div>
<h2 class="Heading js-ToggleCollapseSection" style="-webkit-font-smoothing: antialiased; box-sizing: border-box; color: #333333; font-family: Lora; font-size: 1.625rem; font-weight: 400; line-height: 1.4; margin-bottom: 16px; margin-top: 0px;">
Discussion</h2>
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Propagation of tau aggregation along neuronal networks may mediate the progressive accumulation of pathology observed in tauopathy patients. To measure tau seeding activity in well-characterized human brains, it will be necessary to analyze formaldehyde-fixed tissues. We now present a method for extracting tau seeding activity from miniscule amounts of fixed tissue (approximately .04 mm<span style="box-sizing: border-box; font-size: 12px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">3</span>) to permit direct comparison with tissues stained by IHC.</div>
<div class="Para" id="Par40" style="box-sizing: border-box; font-family: "Open Sans"; margin-bottom: 24px; padding: 0px; word-break: break-word;" xmlns:func="http://oscar.fig.bmc.com" xmlns="http://www.w3.org/1999/xhtml">
We first tested this method in PS19 mice that overexpress full-length human tau (1 N,4R) containing the P301S mutation. We drop-fixed brain samples that had been embedded either in paraffin or PEG and sectioned them coronally for microscopy. We analyzed adjacent 50 μm sections using standard IHC to detect phospho-tau or 1 mm circular punch biopsies of tissue for seeding assays. We homogenized punch biopsies by water-bath sonication in closed tubes, and assayed them in a cellular FRET bioassay system as described previously [<span class="CitationRef" style="box-sizing: border-box;"><a href="https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0442-8#CR10" style="background-color: transparent; box-sizing: border-box; color: #0070bb; cursor: pointer; text-decoration-line: none;">10</a></span>, <span class="CitationRef" style="box-sizing: border-box;"><a href="https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0442-8#CR13" style="background-color: transparent; box-sizing: border-box; color: #0070bb; cursor: pointer; text-decoration-line: none;">13</a></span>].</div>
<div class="Para" id="Par41" style="box-sizing: border-box; font-family: "Open Sans"; margin-bottom: 24px; padding: 0px; word-break: break-word;" xmlns:func="http://oscar.fig.bmc.com" xmlns="http://www.w3.org/1999/xhtml">
Tau seeding activity tracked the development of pathology more efficiently than IHC, with a lower degree of inter-animal variation, and a higher dynamic range. This was perfectly comparable to previously obtained results using fresh frozen tissue [<span class="CitationRef" style="box-sizing: border-box;"><a href="https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0442-8#CR13" style="background-color: transparent; box-sizing: border-box; color: #0070bb; cursor: pointer; text-decoration-line: none;">13</a></span>]. In addition, we detected seeding activity relatively early in the course of disease (1–2 months) and it steadily increased over time. Next, we tested brain tissues from animals previously inoculated with two distinct tau prion strains. We recovered these strains from fixed mouse brain tissue as accurately as we had previously from fresh frozen tissue. Finally, we tested the extraction method in fixed human brain tissue with documented AT8-positive tau pathology, including AD, and readily detected tau seeding activity in cases archived for up to 27 years in formaldehyde.</div>
<section class="Section2 RenderAsSection2" id="Sec24" style="box-sizing: border-box; font-family: "Open Sans";"><h3 class="Heading" style="-webkit-font-smoothing: antialiased; box-sizing: border-box; font-size: 1.125rem; line-height: 1.4; margin-bottom: 4px; margin-top: 0px;">
Seeding activity</h3>
<div class="Para" id="Par42" style="box-sizing: border-box; margin-bottom: 24px; padding: 0px; word-break: break-word;" xmlns:func="http://oscar.fig.bmc.com" xmlns="http://www.w3.org/1999/xhtml">
Our laboratory previously detected tau seeding activity in fresh frozen brain tissue from mouse tauopathy models and human AD cases[<span class="CitationRef" style="box-sizing: border-box;"><a href="https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0442-8#CR11" style="background-color: transparent; box-sizing: border-box; color: #0070bb; cursor: pointer; text-decoration-line: none;">11</a></span>, <span class="CitationRef" style="box-sizing: border-box;"><a href="https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0442-8#CR13" style="background-color: transparent; box-sizing: border-box; color: #0070bb; cursor: pointer; text-decoration-line: none;">13</a></span>]. However, fresh frozen samples are much more difficult to obtain than fixed tissue sections, must be carefully stored at−80 °C, and are very challenging to dissect precisely to isolate specific brain regions. The assay described here accurately quantifies tau seeding from fixed tissue sections over three log orders of signal. Remarkably, in a mouse model from which we sampled tissue at different time points, fixed tissue seeding proved comparable to seeding activity detected in fresh frozen tissue. Thus, we expect that this assay will enable assessment of tau seeding activity in a range of fixed tissues at a similar level of sensitivity to fresh frozen samples.</div>
<div class="Para" id="Par43" style="box-sizing: border-box; margin-bottom: 24px; padding: 0px; word-break: break-word;" xmlns:func="http://oscar.fig.bmc.com" xmlns="http://www.w3.org/1999/xhtml">
Moreover, we detected seeding activity in a small sample of human tauopathy cases that were collected and stored in formalin for over 20 years prior to this study. We observed lower seeding activity in these human samples than in PS19 mice, probably because of the overexpression of an aggregation-prone form of tau in this mouse model. However, the length of fixation may affect the level of seeding observed in samples. Further, differences in seeding activity observed between patients at Braak stage III and V likely reflect differences in the level of tau aggregate burden between these patients, cell loss, or ghost-tangle formation at later disease stages. Given the early detection of seeding activity relative to AT8 staining in PS19 mice, we anticipate that this assay could represent a more sensitive metric of tau pathology. Additional studies in a large number of well-characterized human tissue samples will help address these important questions, and provide additional insight into the progression of seeding activity in human tauopathies.</div>
<div class="Para" id="Par44" style="box-sizing: border-box; margin-bottom: 24px; padding: 0px; word-break: break-word;" xmlns:func="http://oscar.fig.bmc.com" xmlns="http://www.w3.org/1999/xhtml">
Earlier work described a dose-dependent increase in tau seeding activity in the PS19 mouse tauopathy model [<span class="CitationRef" style="box-sizing: border-box;"><a href="https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0442-8#CR13" style="background-color: transparent; box-sizing: border-box; color: #0070bb; cursor: pointer; text-decoration-line: none;">13</a></span>]. However, the regional specificity possible with fresh frozen tissue was limited to gross dissection. We now have reliably isolated and characterized punch biopsies as small as 1 mm diameter x 50 μm (or ~ .04 mm<span style="box-sizing: border-box; font-size: 12px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">3</span>). When we quantified the level of seeding activity at increasing ages vs. the tau pathology observed in adjacent tissue slices using anti-tau AT8 staining, we easily detected tau seeding activity, even in fixed tissue sections with a minimal AT8 signal. For example, when PS19 mice were inoculated with tau strains, we induced strong AT8 pathology with DS9, whereas DS10 produced a weak signal. In both cases, the pathology spread from the site of inoculation to connected regions, as described elsewhere [<span class="CitationRef" style="box-sizing: border-box;"><a href="https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0442-8#CR22" style="background-color: transparent; box-sizing: border-box; color: #0070bb; cursor: pointer; text-decoration-line: none;">22</a></span>]. The fixed tissue seeding assay more readily detected the spread of tau pathology in this propagation model. Furthermore, we readily detected seeding activity in DS10 inoculated mice despite the relatively subtle AT8 staining phenotype induced by this strain (mossy fiber dots). Consequently seeding activity can serve as an important measure of tau pathology when routine AT8 staining reports otherwise minimal pathology. The combination of precise quantification of seeding activity with the ability to sample brain tissue to 1 mm resolution indicates that this method could help define the seeding activity in human brain with remarkably high accuracy.</div>
</section><section class="Section2 RenderAsSection2" id="Sec25" style="box-sizing: border-box;"><h3 class="Heading" style="-webkit-font-smoothing: antialiased; box-sizing: border-box; font-family: "Open Sans"; font-size: 1.125rem; line-height: 1.4; margin-bottom: 4px; margin-top: 0px;">
Detection of tau strains in formaldehyde-fixed tissue</h3>
<div class="Para" id="Par45" style="box-sizing: border-box; font-family: "Open Sans"; margin-bottom: 24px; padding: 0px; word-break: break-word;" xmlns:func="http://oscar.fig.bmc.com" xmlns="http://www.w3.org/1999/xhtml">
Prior experimental work indicates that distinct tau aggregate conformations may underlie different patterns of pathology, rates of progression, and disease phenotypes observed in distinct tauopathies [<span class="CitationRef" style="box-sizing: border-box;"><a href="https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0442-8#CR2" style="background-color: transparent; box-sizing: border-box; color: #0070bb; cursor: pointer; text-decoration-line: none;">2</a></span>, <span class="CitationRef" style="box-sizing: border-box;"><a href="https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0442-8#CR7" style="background-color: transparent; box-sizing: border-box; color: #0070bb; cursor: pointer; text-decoration-line: none;">7</a></span>, <span class="CitationRef" style="box-sizing: border-box;"><a href="https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0442-8#CR22" style="background-color: transparent; box-sizing: border-box; color: #0070bb; cursor: pointer; text-decoration-line: none;">22</a></span>]. Distinct tau strains are associated with different tauopathies [<span class="CitationRef" style="box-sizing: border-box;"><a href="https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0442-8#CR22" style="background-color: transparent; box-sizing: border-box; color: #0070bb; cursor: pointer; text-decoration-line: none;">22</a></span>], and inoculation of unique tau strains produces different patterns and tau pathology rates of progression [<span class="CitationRef" style="box-sizing: border-box;"><a href="https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0442-8#CR16" style="background-color: transparent; box-sizing: border-box; color: #0070bb; cursor: pointer; text-decoration-line: none;">16</a></span>]. We observed that fixed tissue from mice inoculated with DS9 and DS10 produced strain phenotypes identical to the original strains upon inoculation into LM1 biosensor cells. Thus, tau strains are stable upon fixation. We anticipate that formaldehyde-fixed tissues will serve as an invaluable resource to examine the role of strain composition in tauopathies.</div>
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Studies that use traditional IHC techniques to detect tau pathology have provided important insights into the progression and anatomy of macromolecular accumulations of tau assemblies. However, these methods cannot discriminate among distinct strains, nor can they detect submicroscopic tau assemblies. The present assay measures tau pathology based on seeding activity and is also sensitive to strain composition. We anticipate that punch biopsies taken from tissue sections will be useful to measure strain identity with high anatomical precision. By carefully comparing seeding activity and strain composition with standard neuropathology, it should be possible to add new dimensions to analyses of tissue samples from a range of neurodegenerative diseases. In turn, this will facilitate more widespread testing of the putative role of tau prion activity in human tauopathies.</div>
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<span style="font-family: Arial, Helvetica, sans-serif;">snip...see full text ;</span></div>
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<a href="https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0442-8" style="color: #0096ef; cursor: pointer; text-decoration-line: none;">https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0442-8</a></div>
</section></div>
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<a href="http://tauopathies.blogspot.com/2016/12/tau-prions-from-alzheimers-disease-and.html" style="color: #0096ef; cursor: pointer; text-decoration-line: none;">http://tauopathies.blogspot.com/2016/12/tau-prions-from-alzheimers-disease-and.html</a></div>
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<a href="http://tauopathies.blogspot.com/" style="color: #0096ef; cursor: pointer; text-decoration-line: none;">http://tauopathies.blogspot.com/</a></div>
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<a href="http://transmissiblespongiformencephalopathy.blogspot.com/" style="color: #0096ef; cursor: pointer; text-decoration-line: none;">http://transmissiblespongiformencephalopathy.blogspot.com/</a></div>
<div class="Para" id="Par1" style="box-sizing: border-box; margin-bottom: 24px; padding: 0px; word-break: break-word;" xmlns:func="http://oscar.fig.bmc.com" xmlns="http://www.w3.org/1999/xhtml">
<a href="http://chronic-wasting-disease.blogspot.com/" style="color: #0096ef; cursor: pointer; font-size: 10pt; text-decoration-line: none;">http://chronic-wasting-disease.blogspot.com/</a></div>
<div class="Para" id="Par1" style="box-sizing: border-box; margin-bottom: 24px; padding: 0px; word-break: break-word;" xmlns:func="http://oscar.fig.bmc.com" xmlns="http://www.w3.org/1999/xhtml">
<a href="http://scrapie-usa.blogspot.com/" style="color: #0096ef; cursor: pointer; text-decoration-line: none;">http://scrapie-usa.blogspot.com/</a></div>
<div class="Para" id="Par1" style="box-sizing: border-box; margin-bottom: 24px; padding: 0px; word-break: break-word;" xmlns:func="http://oscar.fig.bmc.com" xmlns="http://www.w3.org/1999/xhtml">
<a href="http://bse-atypical.blogspot.com/" style="color: #0096ef; cursor: pointer; text-decoration-line: none;">http://bse-atypical.blogspot.com/</a></div>
<div class="Para" id="Par1" style="box-sizing: border-box; margin-bottom: 24px; padding: 0px; word-break: break-word;" xmlns:func="http://oscar.fig.bmc.com" xmlns="http://www.w3.org/1999/xhtml">
<a href="http://bovineprp.blogspot.com/" style="color: #0096ef; cursor: pointer; text-decoration-line: none;">http://bovineprp.blogspot.com/</a></div>
<div class="Para" id="Par1" style="box-sizing: border-box; margin-bottom: 24px; padding: 0px; word-break: break-word;" xmlns:func="http://oscar.fig.bmc.com" xmlns="http://www.w3.org/1999/xhtml">
<a href="http://transmissible-mink-encephalopathy.blogspot.com/" style="color: #0096ef; cursor: pointer; text-decoration-line: none;">http://transmissible-mink-encephalopathy.blogspot.com/</a></div>
<div class="Para" id="Par1" style="box-sizing: border-box; margin-bottom: 24px; padding: 0px; word-break: break-word;" xmlns:func="http://oscar.fig.bmc.com" xmlns="http://www.w3.org/1999/xhtml">
<a href="http://creutzfeldt-jakob-disease.blogspot.com/" style="color: #0096ef; cursor: pointer; text-decoration-line: none;">http://creutzfeldt-jakob-disease.blogspot.com/</a></div>
<div class="Para" id="Par1" style="box-sizing: border-box; margin-bottom: 24px; padding: 0px; word-break: break-word;" xmlns:func="http://oscar.fig.bmc.com" xmlns="http://www.w3.org/1999/xhtml">
Terry S. Singeltary Sr.</div>
</div>
</section></div>
Terry S. Singeltary Sr.http://www.blogger.com/profile/06986622967539963260noreply@blogger.com0tag:blogger.com,1999:blog-6491423064023155264.post-65746031173939289332016-12-06T19:42:00.001-06:002016-12-06T19:42:40.154-06:00Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells<h1 id="article-title-1" itemprop="headline">
Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells</h1>
<div class="contributors">
<ol class="contributor-list" id="contrib-group-1">
<li class="contributor" id="contrib-1" itemprop="author" itemscope="itemscope" itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search" href="http://www.pnas.org/search?author1=Amanda+L.+Woerman&sortspec=date&submit=Submit">Amanda L. Woerman</a></span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-1" id="xref-aff-1-1"><sup><span style="font-size: x-small;">a</span></sup></a><span class="xref-sep">,</span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-2" id="xref-aff-2-1"><sup><span style="font-size: x-small;">b</span></sup></a><span class="xref-sep">,</span><a class="xref-fn" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#fn-4" id="xref-fn-4-1"><sup><span style="font-size: x-small;">1</span></sup></a>, </li>
<li class="contributor" id="contrib-2" itemprop="author" itemscope="itemscope" itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search" href="http://www.pnas.org/search?author1=Atsushi+Aoyagi&sortspec=date&submit=Submit">Atsushi Aoyagi</a></span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-1" id="xref-aff-1-2"><sup><span style="font-size: x-small;">a</span></sup></a><span class="xref-sep">,</span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-3" id="xref-aff-3-1"><sup><span style="font-size: x-small;">c</span></sup></a><span class="xref-sep">,</span><a class="xref-fn" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#fn-4" id="xref-fn-4-2"><sup><span style="font-size: x-small;">1</span></sup></a>, </li>
<li class="contributor" id="contrib-3" itemprop="author" itemscope="itemscope" itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search" href="http://www.pnas.org/search?author1=Smita+Patel&sortspec=date&submit=Submit">Smita Patel</a></span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-1" id="xref-aff-1-3"><sup><span style="font-size: x-small;">a</span></sup></a>, </li>
<li class="contributor" id="contrib-4" itemprop="author" itemscope="itemscope" itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search" href="http://www.pnas.org/search?author1=Sabeen+A.+Kazmi&sortspec=date&submit=Submit">Sabeen A. Kazmi</a></span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-1" id="xref-aff-1-4"><sup><span style="font-size: x-small;">a</span></sup></a>, </li>
<li class="contributor" id="contrib-5" itemprop="author" itemscope="itemscope" itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search" href="http://www.pnas.org/search?author1=Iryna+Lobach&sortspec=date&submit=Submit">Iryna Lobach</a></span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-4" id="xref-aff-4-1"><sup><span style="font-size: x-small;">d</span></sup></a>, </li>
<li class="contributor" id="contrib-6" itemprop="author" itemscope="itemscope" itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search" href="http://www.pnas.org/search?author1=Lea+T.+Grinberg&sortspec=date&submit=Submit">Lea T. Grinberg</a></span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-2" id="xref-aff-2-2"><sup><span style="font-size: x-small;">b</span></sup></a><span class="xref-sep">,</span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-5" id="xref-aff-5-1"><sup><span style="font-size: x-small;">e</span></sup></a>, </li>
<li class="contributor" id="contrib-7" itemprop="author" itemscope="itemscope" itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search" href="http://www.pnas.org/search?author1=Ann+C.+McKee&sortspec=date&submit=Submit">Ann C. McKee</a></span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-6" id="xref-aff-6-1"><sup><span style="font-size: x-small;">f</span></sup></a><span class="xref-sep">,</span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-7" id="xref-aff-7-1"><sup><span style="font-size: x-small;">g</span></sup></a><span class="xref-sep">,</span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-8" id="xref-aff-8-1"><sup><span style="font-size: x-small;">h</span></sup></a><span class="xref-sep">,</span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-9" id="xref-aff-9-1"><sup><span style="font-size: x-small;">i</span></sup></a><span class="xref-sep">,</span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-10" id="xref-aff-10-1"><sup><span style="font-size: x-small;">j</span></sup></a>, </li>
<li class="contributor" id="contrib-8" itemprop="author" itemscope="itemscope" itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search" href="http://www.pnas.org/search?author1=William+W.+Seeley&sortspec=date&submit=Submit">William W. Seeley</a></span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-2" id="xref-aff-2-3"><sup><span style="font-size: x-small;">b</span></sup></a><span class="xref-sep">,</span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-5" id="xref-aff-5-2"><sup><span style="font-size: x-small;">e</span></sup></a>, </li>
<li class="contributor" id="contrib-9" itemprop="author" itemscope="itemscope" itemtype="http://schema.org/Person"><span class="name" itemprop="name"><a class="name-search" href="http://www.pnas.org/search?author1=Steven+H.+Olson&sortspec=date&submit=Submit">Steven H. Olson</a></span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-1" id="xref-aff-1-5"><sup><span style="font-size: x-small;">a</span></sup></a><span class="xref-sep">,</span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-2" id="xref-aff-2-4"><sup><span style="font-size: x-small;">b</span></sup></a>, and </li>
<li class="last" id="contrib-10"><span class="name"><a class="name-search" href="http://www.pnas.org/search?author1=Stanley+B.+Prusiner&sortspec=date&submit=Submit">Stanley B. Prusiner</a></span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-1" id="xref-aff-1-6"><sup><span style="font-size: x-small;">a</span></sup></a><span class="xref-sep">,</span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-2" id="xref-aff-2-5"><sup><span style="font-size: x-small;">b</span></sup></a><span class="xref-sep">,</span><a class="xref-aff" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#aff-11" id="xref-aff-11-1"><sup><span style="font-size: x-small;">k</span></sup></a><span class="xref-sep">,</span><a class="xref-corresp" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#corresp-1" id="xref-corresp-1-1"><sup><span style="font-size: x-small;">2</span></sup></a></li>
</ol>
<div class="expand menu_head affil-head">
<a href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#" style="display: block;" title=""> Author Affiliations</a></div>
<ol class="collapse menu_body affil-body shown">
<li class="aff"><a href="https://www.blogger.com/null" id="aff-1" name="aff-1"></a><address>
<sup><span style="font-size: x-small;">a</span></sup>Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, <span class="institution">University of California, San Francisco</span>, <span class="addr-line">CA</span> 94143; </address>
</li>
<li class="aff"><a href="https://www.blogger.com/null" id="aff-2" name="aff-2"></a><address>
<sup><span style="font-size: x-small;">b</span></sup>Department of Neurology, <span class="institution">University of California, San Francisco</span>, <span class="addr-line">CA</span> 94143; </address>
</li>
<li class="aff"><a href="https://www.blogger.com/null" id="aff-3" name="aff-3"></a><address>
<sup><span style="font-size: x-small;">c</span></sup>Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan; </address>
</li>
<li class="aff"><a href="https://www.blogger.com/null" id="aff-4" name="aff-4"></a><address>
<sup><span style="font-size: x-small;">d</span></sup>Department of Epidemiology and Biostatistics, <span class="institution">University of California, San Francisco</span>, <span class="addr-line">CA</span> 94143; </address>
</li>
<li class="aff"><a href="https://www.blogger.com/null" id="aff-5" name="aff-5"></a><address>
<sup><span style="font-size: x-small;">e</span></sup>Department of Pathology, <span class="institution">University of California, San Francisco</span>, <span class="addr-line">CA</span> 94143; </address>
</li>
<li class="aff"><a href="https://www.blogger.com/null" id="aff-6" name="aff-6"></a><address>
<sup><span style="font-size: x-small;">f</span></sup>Chronic Traumatic Encephalopathy Program, Alzheimer’s Disease Center, <span class="institution">Boston University School of Medicine</span>, Boston, <span class="addr-line">MA</span> 02118; </address>
</li>
<li class="aff"><a href="https://www.blogger.com/null" id="aff-7" name="aff-7"></a><address>
<sup><span style="font-size: x-small;">g</span></sup>Department of Neurology, <span class="institution">Boston University School of Medicine</span>, Boston, <span class="addr-line">MA</span> 02118; </address>
</li>
<li class="aff"><a href="https://www.blogger.com/null" id="aff-8" name="aff-8"></a><address>
<sup><span style="font-size: x-small;">h</span></sup>Department of Pathology, <span class="institution">Boston University School of Medicine</span>, Boston, <span class="addr-line">MA</span> 02118; </address>
</li>
<li class="aff"><a href="https://www.blogger.com/null" id="aff-9" name="aff-9"></a><address>
<sup><span style="font-size: x-small;">i</span></sup>Veterans Affairs Boston Healthcare System, <span class="institution">US Department of Veterans Affairs</span>, Jamaica Plain, <span class="addr-line">MA</span> 02130; </address>
</li>
<li class="aff"><a href="https://www.blogger.com/null" id="aff-10" name="aff-10"></a><address>
<sup><span style="font-size: x-small;">j</span></sup><span class="institution">US Department of Veterans Affairs Medical Center</span>, Bedford, <span class="addr-line">MA</span> 01730; </address>
</li>
<li class="aff"><a href="https://www.blogger.com/null" id="aff-11" name="aff-11"></a><address>
<sup><span style="font-size: x-small;">k</span></sup>Department of Biochemistry and Biophysics, <span class="institution">University of California, San Francisco</span>, <span class="addr-line">CA</span> 94143 </address>
</li>
</ol>
<ol class="fn-track">
<li class="fn-con" id="fn-1"><div id="p-1">
Contributed by Stanley B. Prusiner, October 6, 2016 (sent for review August 5, 2016; reviewed by Robert H. Brown Jr. and David Westaway) </div>
</li>
</ol>
</div>
<div class="cb-section cb-views">
<ul class="cit-views primary-views"></ul>
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<li class="abstract active"><span class="variant-indicator">Abstract</span></li>
<li class="notice full-text"><a href="http://www.pnas.org/content/early/2016/11/22/1616344113.full" rel="view-full-text">Full Text</a></li>
<li class="author-tab"><a href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#">Authors & Info</a></li>
<li class="figures-only"><a href="http://www.pnas.org/content/early/2016/11/22/1616344113.figures-only" rel="view-figures-only">Figures</a></li>
<li class="si"><a class="dslink-supporting-information" href="http://www.pnas.org/content/early/2016/11/22/1616344113/suppl/DCSupplemental" rel="supplemental-data">SI</a></li>
<li class="metrics"><a href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#">Metrics</a></li>
<li class="related"><a href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract/?tab=related">Related Content</a></li>
<li class="notice full-text-pdf"><a href="http://www.pnas.org/content/early/2016/11/22/1616344113.full.pdf" rel="view-full-text.pdf">PDF</a></li>
<li class="full-si-pdf"><a href="http://www.pnas.org/content/early/2016/11/22/1616344113.full.pdf?with-ds=yes" rel="view-full-text-pdf-with-supplemental-data">PDF + SI</a></li>
</ol>
<div style="clear: both;">
</div>
</div>
<div class="executive-summary significance-box">
<h2>
Significance</h2>
<div id="p-6">
The progressive nature of neurodegenerative diseases is due to the spread of prions, misfolded infectious proteins, in the brain. In tauopathies, the protein tau misfolds, causing several diseases, including Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). Here we created a panel of mammalian cell lines expressing a fragment of tau fused to yellow fluorescent protein. Each cell line selectively detects tau prions that are misfolded into self-propagating conformations; such cells permit identification of minute differences among tauopathies. For example, tau prions in AD and CTE are distinct from prions in other tauopathies such as Pick’s disease and progressive supranuclear palsy. These insights are likely to contribute to the development of future therapeutics. </div>
</div>
<div class="section abstract" id="abstract-2">
<h2>
Abstract</h2>
<div id="p-7">
Tau prions are thought to aggregate in the central nervous system, resulting in neurodegeneration. Among the tauopathies, Alzheimer’s disease (AD) is the most common, whereas argyrophilic grain disease (AGD), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick’s disease (PiD), and progressive supranuclear palsy (PSP) are less prevalent. Brain extracts from deceased individuals with PiD, a neurodegenerative disorder characterized by three-repeat (3R) tau prions, were used to infect HEK293T cells expressing 3R tau fused to yellow fluorescent protein (YFP). Extracts from AGD, CBD, and PSP patient samples, which contain four-repeat (4R) tau prions, were transmitted to HEK293 cells expressing 4R tau fused to YFP. These studies demonstrated that prion propagation in HEK cells requires isoform pairing between the infecting prion and the recipient substrate. Interestingly, tau aggregates in AD and CTE, containing both 3R and 4R isoforms, were unable to robustly infect either 3R- or 4R-expressing cells. However, AD and CTE prions were able to replicate in HEK293T cells expressing both 3R and 4R tau. Unexpectedly, increasing the level of 4R isoform expression alone supported the propagation of both AD and CTE prions. These results allowed us to determine the levels of tau prions in AD and CTE brain extracts. </div>
</div>
<ul class="kwd-group">
<li class="kwd"><span><a class="kwd-search" href="http://www.pnas.org/search?fulltext=argyrophilic+grain+disease&sortspec=date&submit=Submit&andorexactfulltext=phrase">argyrophilic grain disease</a></span></li>
<li class="kwd"><span><a class="kwd-search" href="http://www.pnas.org/search?fulltext=corticobasal+degeneration&sortspec=date&submit=Submit&andorexactfulltext=phrase">corticobasal degeneration</a></span></li>
<li class="kwd"><span><a class="kwd-search" href="http://www.pnas.org/search?fulltext=Pick%E2%80%99s+disease&sortspec=date&submit=Submit&andorexactfulltext=phrase">Pick’s disease</a></span></li>
<li class="kwd"><span><a class="kwd-search" href="http://www.pnas.org/search?fulltext=progressive+supranuclear+palsy&sortspec=date&submit=Submit&andorexactfulltext=phrase">progressive supranuclear palsy</a></span></li>
<li class="kwd"><span><a class="kwd-search" href="http://www.pnas.org/search?fulltext=tauopathies&sortspec=date&submit=Submit&andorexactfulltext=phrase">tauopathies</a></span></li>
</ul>
<h2 class="section fn-group">
Footnotes</h2>
<div class="section fn-group">
<ul class="pnas-footnotes">
<li class="fn-equal" id="fn-4"><div id="p-4">
<a class="rev-xref" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#xref-fn-4-1">↵</a><sup><span style="font-size: x-small;">1</span></sup>A.L.W. and A.A. contributed equally to this work. </div>
</li>
<li class="corresp" id="corresp-1"><a class="rev-xref" href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract#xref-corresp-1-1">↵</a><sup><span style="font-size: x-small;">2</span></sup>To whom correspondence should be addressed. Email: <a href="https://www.blogger.com/null">stanley.prusiner@ucsf.edu</a>. </li>
</ul>
</div>
<ul>
<li class="fn-other" id="fn-2"><div id="p-2">
Author contributions: A.L.W., A.A., S.H.O., and S.B.P. designed research; A.L.W., A.A., S.P., S.A.K., and L.T.G. performed research; I.L., L.T.G., A.C.M., and W.W.S. contributed new reagents/analytic tools; A.L.W., A.A., S.P., I.L., S.H.O., and S.B.P. analyzed data; and A.L.W., A.A., S.H.O., and S.B.P. wrote the paper. </div>
</li>
<li class="fn-other" id="fn-3"><div id="p-3">
Reviewers: R.H.B., University of Massachusetts Medical School; and D.W., University of Alberta.</div>
</li>
<li class="fn-conflict" id="fn-13"><div id="p-74">
Conflict of interest statement: A provisional patent application has been submitted in connection with this work. Inventors include A.L.W., A.A., S.P., S.A.K., S.H.O., and S.B.P. </div>
</li>
<li class="fn-supplementary-material" id="fn-14"><div id="p-75">
This article contains supporting information online at <a class="in-nw-vis" href="http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1616344113/-/DCSupplemental" target="_blank">www.pnas.org/lookup/suppl/doi:10.1073/pnas.1616344113/-/DCSupplemental</a>. </div>
</li>
</ul>
<div class="fn-supplementary-material">
<br /></div>
<div class="fn-supplementary-material">
<a href="http://www.pnas.org/content/early/2016/11/22/1616344113.abstract">http://www.pnas.org/content/early/2016/11/22/1616344113.abstract</a></div>
<div class="fn-supplementary-material">
<br /></div>
<div class="fn-supplementary-material">
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<span style="font-size: 14px;"><strong>The Prion Institute focuses on the following areas of research excellence: protein folding and misfolding; pathobiology of TSEs; surveillance and control; and TSEs and society. </strong></span></div>
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<span style="font-family: georgia,serif;"><span style="font-size: 14px;">The Alberta Prion Research Institute (Prion Institute) and the Alzheimer Society of Alberta and Northwest Territories (ASANT) present the Alberta Alzheimer Research Program (AARP). The AARP allows qualified Alberta investigators to seek funding for research directly related to Alzheimer’s disease in areas related to understanding the fundamental mechanisms of the disease and/or improving the quality of life of those with Alzheimer’s disease. There are two streams for grants: Young Investigator Grants and Regular Research Grants. Young Investigator Grants are available to Alberta researchers who are within five years of their first appointment after completing their research training. These grants are for up to $200,000 with a term of up to three years. Regular Research Grants are available to all Alberta researchers, including young investigators. These grants are for up to $150,000 with a term of up to three years.</span></span><br /><br /><span style="font-size: 14px;"><span style="font-family: georgia,serif;"><strong>Application Deadline:</strong> January 16, 2017</span></span></div>
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<span style="font-size: 14px;"><a href="http://prioninstitute.ca/admin/ckfinder/userfiles/files/AARP_Guidelines.pdf" rel="noopener noreferrer" target="_blank">Program Guidelines</a></span></div>
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<span style="font-size: 14px;"><a href="http://prioninstitute.ca/admin/ckfinder/userfiles/files/AARP_Funding.xlsx" rel="noopener noreferrer" target="_blank">Funding Declaration</a></span></div>
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<a href="http://prioninstitute.ca/admin/ckfinder/userfiles/files/AARP_Budget.xlsx" rel="noopener noreferrer" target="_blank"><span style="font-size: 14px;">Budget Spreadsheet</span></a></div>
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<img alt="" src="data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAK8AAAASCAIAAACipBmJAAAAVElEQVRoge3SoQ3AMBAEQfffqsmDt15WSOCVkICRpoAFu3Y17OrqWZ9H8BNuINxAuIFwA+EGwg2EGwg3EG4g3EC4gXAD4QbCDYQbiOpZZy6cuXOfFw/0oO2oShRnAAAAAElFTkSuQmCC" /></div>
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<span style="font-family: georgia,serif;"><span style="font-size: 14px;"><span style="font-size: 16px;"><span style="color: firebrick;"><span style="font-family: georgia,serif;">EXPLORATIONS</span></span></span></span></span></div>
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<br /><span style="font-family: georgia,serif;"><span style="font-size: 14px;">The Explorations Program allows Alberta-based investigators to seek funding for research directly related to prion diseases and prion-like human neurodegenerative diseases and dementias. The research themes for this program are protein folding and misfolding in prion diseases, the pathobiology of transmissible spongiform encephalopathies (TSEs), surveillance and control of prion diseases, TSEs and society, protein folding and misfolding in prion-like human neurodegenerative diseases, and prion-like mechanisms in human neurodegenerative diseases. The Alberta Prion Research Institute offers two tiers of funding for the Explorations competition: grants of up to $200,000 for a maximum of two years and grants of up to $500,000 for a maximum of three years.</span></span><br /><br /><span style="font-size: 14px;"><strong>Application Deadline:</strong> no current competition</span></div>
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<br /><img alt="" src="data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAK8AAAASCAIAAACipBmJAAAAVElEQVRoge3SoQ3AMBAEQfffqsmDt15WSOCVkICRpoAFu3Y17OrqWZ9H8BNuINxAuIFwA+EGwg2EGwg3EG4g3EC4gXAD4QbCDYQbiOpZZy6cuXOfFw/0oO2oShRnAAAAAElFTkSuQmCC" /></div>
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<span style="font-family: georgia,serif;"><span style="font-size: 14px;"><span style="font-size: 16px;"><span style="color: firebrick;"><span style="font-family: georgia,serif;">SPECIFIED RISK MATERIALS PROGRAM</span></span></span></span></span></div>
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<br /><span style="font-family: georgia,serif;"><span style="font-size: 14px;">The Specified Risk Materials Program is intended to allow qualified investigators to seek funding for research directly related to the following areas of specified risk materials (SRM): detection of prions in complex matrices; SRM as feedstock for processes and products; disposition and disposal methods; cost benefit estimates of existing or new disposition and disposal methodologies; risk assessment; risk communication about SRM and risks and benefits of disposition and disposal of SRM; and other. Funding is accessible for all relevant fields of inquiry in the themes as described in the guideline to develop innovative disposition and disposal methods and/or uses of specified risk materials. This competition will support grants of up to $500,000 for a period of up to three years. </span></span><br /><br /><span style="font-size: 14px;"><strong>Application Deadline:</strong> no current competition</span></div>
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<img alt="" src="data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAK8AAAASCAIAAACipBmJAAAAVElEQVRoge3SoQ3AMBAEQfffqsmDt15WSOCVkICRpoAFu3Y17OrqWZ9H8BNuINxAuIFwA+EGwg2EGwg3EG4g3EC4gXAD4QbCDYQbiOpZZy6cuXOfFw/0oO2oShRnAAAAAElFTkSuQmCC" /></div>
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<span style="font-family: georgia,serif;"><span style="font-size: 14px;"><span style="font-size: 16px;"><span style="color: firebrick;"><span style="font-family: georgia,serif;">RESEARCH TEAM PROGRAM</span></span></span></span></span><br /> </div>
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<span style="font-family: georgia,serif;"><span style="font-size: 14px;">The Research Team Program allows teams of qualified investigators to seek funding for research directly related to prion diseases and prion-like human neurodegenerative diseases and dementias. The research themes for this program are protein folding and misfolding in prion diseases, the pathobiology of TSEs, surveillance and control of prion diseases, TSEs and society, protein folding and misfolding in prion-like human neurodegenerative diseases and prion-like mechanisms in the pathobiology of prion-like human neurodegenerative diseases. The program is designed to encourage collaboration within Alberta and between Alberta-based investigators and researchers outside of Alberta. The team of researchers must be from at least two different research institutions. The Alberta Prion Research Institute provides up to $750,000 for a team grant over a maximum of three years.<br /><br /><strong>Application Deadline:</strong> no current competition</span></span></div>
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<br /><img alt="" src="data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAK8AAAASCAIAAACipBmJAAAAVElEQVRoge3SoQ3AMBAEQfffqsmDt15WSOCVkICRpoAFu3Y17OrqWZ9H8BNuINxAuIFwA+EGwg2EGwg3EG4g3EC4gXAD4QbCDYQbiOpZZy6cuXOfFw/0oO2oShRnAAAAAElFTkSuQmCC" /></div>
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<span style="font-family: georgia,serif;"><span style="font-size: 14px;"><span style="font-size: 16px;"><span style="color: firebrick;"><span style="font-family: georgia,serif;">IDeal PROGRAM</span></span></span></span></span></div>
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<span style="font-family: georgia,serif;"><span style="font-size: 14px;">The IDeal Program, also known as the Innovation and Delivery Program, was created to encourage collaboration among industry, Alberta universities and research institutions. The Alberta Prion Research Institute invites applications for research and development projects undertaken by Alberta-based private sector organizations or public sector researchers and their private sector partners. A private sector partner may be a company, an industry association or similar body. Direct project costs are shared by private sector partners and the funders. IDeal grants are typically of an applied nature and directed at a specific challenge identified by the private sector partner and the industry. Themes accessible for funding are:</span></span></div>
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<li><span style="font-family: georgia,serif;"><span style="font-size: 14px;">Protein folding and misfolding in prion diseases;</span></span></li>
<li><span style="font-family: georgia,serif;"><span style="font-size: 14px;">The pathobiology of TSEs;</span></span></li>
<li><span style="font-family: georgia,serif;"><span style="font-size: 14px;">Surveillance and control of prion diseases;</span></span></li>
<li><span style="font-family: georgia,serif;"><span style="font-size: 14px;">Diagnostic technologies;</span></span></li>
<li><span style="font-family: georgia,serif;"><span style="font-size: 14px;">Solutions to enhance market access;</span></span></li>
<li><span style="font-family: georgia,serif;"><span style="font-size: 14px;">Innovative disposal and/or uses of specified risk material;</span></span></li>
<li><span style="font-family: georgia,serif;"><span style="font-size: 14px;">TSEs and society;</span></span></li>
<li><span style="font-family: georgia,serif;"><span style="font-size: 14px;">Protein folding and misfolding in prion-like human neurodegenerative diseases; and</span></span></li>
<li><span style="font-family: georgia,serif;"><span style="font-size: 14px;">Prion-like mechanisms in human neurodegenerative diseases.</span></span><br /> </li>
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<span style="font-size: 14px;"><span style="font-family: georgia,serif;">Funding may be up to $500,000. Projects may range from one to three years in duration.</span></span><br /><br /><span style="font-size: 14px;"><span style="font-family: georgia,serif;"><strong>Application Deadline:</strong> continuous intake</span></span></div>
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<br /><img alt="" src="data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAK8AAAASCAIAAACipBmJAAAAVElEQVRoge3SoQ3AMBAEQfffqsmDt15WSOCVkICRpoAFu3Y17OrqWZ9H8BNuINxAuIFwA+EGwg2EGwg3EG4g3EC4gXAD4QbCDYQbiOpZZy6cuXOfFw/0oO2oShRnAAAAAElFTkSuQmCC" /></div>
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<span style="font-family: georgia,serif;"><span style="font-size: 14px;"><span style="font-size: 16px;"><span style="color: firebrick;"><span style="font-family: georgia,serif;">GUEST SPEAKER SUPPORT PROGRAM</span></span></span></span></span><br /> </div>
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<span style="font-family: georgia,serif;"><span style="font-size: 14px;">The Guest Speaker Support Program is designed to disseminate knowledge to the Alberta research and science community by offering funding to help bring notable researchers in prion and protein misfolding science to Alberta to present lectures and to participate in panel discussions. These experts assist with planning or implementing collaborative research programs and/or explore and evaluate recent breakthroughs in prion science. Speakers might be involved in research related activities or public studies or both. Funds are provided primarily to offset the costs of travel and accommodation for guest speakers. Support of up to $1,500 is provided for speakers travelling within North America, and up to $2,500 is provided for speakers travelling from outside North America. In some cases, the Alberta Prion Research Institute will consider application for a contribution toward the cost of conducting an associated conference, symposia or workshop.</span></span><br /><br /><span style="font-size: 14px;"><span style="font-family: georgia,serif;"><strong>Application Deadline:</strong> continuous intake</span></span></div>
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<img alt="" src="data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAK8AAAASCAIAAACipBmJAAAAVElEQVRoge3SoQ3AMBAEQfffqsmDt15WSOCVkICRpoAFu3Y17OrqWZ9H8BNuINxAuIFwA+EGwg2EGwg3EG4g3EC4gXAD4QbCDYQbiOpZZy6cuXOfFw/0oO2oShRnAAAAAElFTkSuQmCC" /></div>
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<span style="font-family: georgia,serif;"><span style="font-size: 14px;"><span style="font-size: 16px;"><span style="color: firebrick;"><span style="font-family: georgia,serif;">EXPANDING HORIZONS PROGRAM</span></span></span></span></span></div>
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<span style="font-family: georgia,serif;"><span style="font-size: 14px;">The Expanding Horizons Program is a professional development program for graduate students and postdoctoral fellows who are currently working on prion research. The objective of this program is to provide research trainees with access to mentoring in order to develop skills and knowledge that are applicable both within and outside of the lab. Seminars focus on career development in research as well as other careers they might undertake such as those in industry or policy making. Ensuring trainees are skilled in topics like lab management, networking, communicating, interview skills and grant crafting will benefit their futures as well as the future of prion research.</span></span></div>
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<a href="http://prioninstitute.ca/content/programs" rel="noopener noreferrer" target="_blank">http://prioninstitute.ca/content/programs</a></div>
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<span style="color: black; font-size: 12pt; margin: 0px;">Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease<br /><br /> *** Singeltary comment PLoS ***<br /><br /> Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, </span> <div style="margin: 0px;">
<span style="color: black; font-size: 12pt; margin: 0px;">what if ? <br /><br /> Posted by flounder on 05 Nov 2014 at 21:27 GMT<br /><br /><a href="http://www.plosone.org/annotation/listThread.action?root=82860" rel="noopener noreferrer" target="_blank"><span style="color: blue; font-family: Calibri;"></span></a><span style="color: blue; font-family: Calibri;"><a href="http://www.plosone.org/annotation/listThread.action?root=82860" rel="noopener noreferrer" target="_blank"><span style="color: #cc6611;"></span></a><span style="color: #cc6611;"><a href="http://www.plosone.org/annotation/listThread.action?root=82860" target="_blank">http://www.plosone.org/annotation/listThread.action?root=82860</a></span></span> <br /><br /> Sunday, November 22, 2015 <br /><br /> *** Effect of heating on the stability of amyloid A (AA) fibrils and the intra- and cross-species transmission of AA amyloidosis Abstract <br /><br /> Amyloid A (AA) amyloidosis is a protein misfolding disease characterized by extracellular deposition of AA fibrils. AA fibrils are found in several tissues from food animals with AA amyloidosis. For hygienic purposes, heating is widely used to inactivate microbes in food, but it is uncertain whether heating is sufficient to inactivate AA fibrils and prevent intra- or cross-species transmission. We examined the effect of heating (at 60 °C or 100 °C) and autoclaving (at 121 °C or 135 °C) on murine and bovine AA fibrils using Western blot analysis, transmission electron microscopy (TEM), and mouse model transmission experiments. TEM revealed that a mixture of AA fibrils and amorphous aggregates appeared after heating at 100 °C, whereas autoclaving at 135 °C produced large amorphous aggregates. AA fibrils retained antigen specificity in Western blot analysis when heated at 100 °C or autoclaved at 121 °C, but not when autoclaved at 135 °C. Transmissible pathogenicity of murine and bovine AA fibrils subjected to heating (at 60 °C or 100 °C) was significantly stimulated and resulted in amyloid deposition in mice. Autoclaving of murine AA fibrils at 121 °C or 135 °C significantly decreased amyloid deposition. Moreover, amyloid deposition in mice injected with murine AA fibrils was more severe than that in mice injected with bovine AA fibrils. Bovine AA fibrils autoclaved at 121 °C or 135 °C did not induce amyloid deposition in mice. These results suggest that AA fibrils are relatively heat stable and that similar to prions, autoclaving at 135 °C is required to destroy the pathogenicity of AA fibrils. These findings may contribute to the prevention of AA fibril transmission through food materials to different animals and especially to humans. <br /><br /> Purchase options Price * Issue Purchase USD 511.00 Article Purchase USD 54.00 <br /><br /><a href="http://www.tandfonline.com/doi/abs/10.3109/13506129.2015.1095735?journalCode=iamy20" rel="noopener noreferrer" target="_blank"><span style="color: blue; font-family: Calibri;"></span></a><span style="color: blue; font-family: Calibri;"><a href="http://www.tandfonline.com/doi/abs/10.3109/13506129.2015.1095735?journalCode=iamy20" rel="noopener noreferrer" target="_blank"><span style="color: #cc6611;"></span></a><span style="color: #cc6611;"><a href="http://www.tandfonline.com/doi/abs/10.3109/13506129.2015.1095735?journalCode=iamy20" target="_blank">http://www.tandfonline.com/doi/abs/10.3109/13506129.2015.1095735?journalCode=iamy20</a></span></span><br /><u><span style="color: #cc6611;"><br /></span></u><a href="http://betaamyloidcjd.blogspot.com/2015/11/effect-of-heating-on-stability-of.html" rel="noopener noreferrer" target="_blank"><span style="font-family: Calibri;"></span></a><span style="font-family: Calibri;"><a href="http://betaamyloidcjd.blogspot.com/2015/11/effect-of-heating-on-stability-of.html" rel="noopener noreferrer" target="_blank"><span style="color: #cc6611;"></span></a><span style="color: #cc6611;"><a href="http://betaamyloidcjd.blogspot.com/2015/11/effect-of-heating-on-stability-of.html" target="_blank">http://betaamyloidcjd.blogspot.com/2015/11/effect-of-heating-on-stability-of.html</a></span></span> </span></div>
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<span style="color: black; font-size: 12pt; margin: 0px;">SWISS MEDICAL WEEKLY<br /><br /> Alzheimer-type brain pathology may be transmitted by grafts of dura mater 26/01/2016 Singeltary comment ;<br /><br /><a href="http://blog.smw.ch/alzheimer-type-brain-pathology-may-be-transmitted-by-grafts-of-dura-mater/#comment-89016" rel="noopener noreferrer" target="_blank"><span style="color: blue; font-family: Calibri;"></span></a><span style="color: blue; font-family: Calibri;"><a href="http://blog.smw.ch/alzheimer-type-brain-pathology-may-be-transmitted-by-grafts-of-dura-mater/#comment-89016" rel="noopener noreferrer" target="_blank"><span style="color: #cc6611;"></span></a><span style="color: #cc6611;"><a href="http://blog.smw.ch/alzheimer-type-brain-pathology-may-be-transmitted-by-grafts-of-dura-mater/#comment-89016" target="_blank">http://blog.smw.ch/alzheimer-type-brain-pathology-may-be-transmitted-by-grafts-of-dura-mater/#comment-89016</a></span></span><br /><u><span style="color: #cc6611;"><br /></span></u> re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy <br /><br /> Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015) <br /><br /> snip...see full Singeltary Nature comment here; <br /><br /><a href="http://www.nature.com/nature/journal/v525/n7568/full/nature15369.html#/comments" rel="noopener noreferrer" target="_blank"><span style="color: blue; font-family: Calibri;"></span></a><span style="color: blue; font-family: Calibri;"><a href="http://www.nature.com/nature/journal/v525/n7568/full/nature15369.html#/comments" rel="noopener noreferrer" target="_blank"><span style="color: #cc6611;"></span></a><span style="color: #cc6611;"><a href="http://www.nature.com/nature/journal/v525/n7568/full/nature15369.html#/comments" target="_blank">http://www.nature.com/nature/journal/v525/n7568/full/nature15369.html#/comments</a></span></span> </span></div>
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Sunday, December 04, 2016</h2>
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Heidenhain variant of Creutzfeldt–Jakob disease in a patient who had bovine bioprosthetic valve implantation </h3>
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<span style="margin: 0px;"><span style="font-family: Calibri;">Year : 2016 | Volume : 64 | Issue : 10 | Page : 767-769 <span style="font-family: Arial, Helvetica, sans-serif;"></span></span></span></div>
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PRION2017 DECIPHERING NEURODEGENERATIVE DISORDERS 23 – 26 May 2017 Edinburgh </h3>
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<a href="http://prionprp.blogspot.com/2016/12/prion2017-deciphering-neurodegenerative.html" rel="noopener noreferrer" target="_blank">http://prionprp.blogspot.com/2016/12/prion2017-deciphering-neurodegenerative.html</a></div>
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Saturday, December 03, 2016</h2>
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TEXAS CHRONIC WASTING DISEASE CWD TSE PRION UPDATE 35 CASES TO DATE</h3>
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<a href="http://chronic-wasting-disease.blogspot.com/2016/12/texas-chronic-wasting-disease-cwd-tse.html" rel="noopener noreferrer" target="_blank">http://chronic-wasting-disease.blogspot.com/2016/12/texas-chronic-wasting-disease-cwd-tse.html</a></div>
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<a href="https://www.blogger.com/null" name="3298496127376768657" rel="noopener noreferrer" target="_blank"></a><span style="color: black; font-family: "Arial",sans-serif; margin: 0px;"><span style="font-size: x-small;">The European Union summary report on data of the surveillance of ruminants for the presence of transmissible spongiform encephalopathies (TSEs) in 2015</span></span></h3>
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<span style="color: black; font-size: 12pt; margin: 0px;">Transmissibility of Gerstmann–Sträussler–Scheinker syndrome in rodent models: new insights into the molecular underpinnings of prion infectivity</span></div>
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<span style="color: black; font-size: 12pt; margin: 0px;"><span style="color: black; font-family: "Arial",sans-serif; font-size: 10pt; margin: 0px;">Saturday, July 23, 2016 <br /><br /> BOVINE SPONGIFORM ENCEPHALOPATHY BSE TSE PRION SURVEILLANCE, TESTING, AND SRM REMOVAL UNITED STATE OF AMERICA UPDATE JULY 2016 <br /><br /><a href="http://bovineprp.blogspot.com/2016/07/bovine-spongiform-encephalopathy-bse.html" rel="noopener noreferrer" target="_blank"><span style="color: blue;"></span></a><span style="color: blue;"><a href="http://bovineprp.blogspot.com/2016/07/bovine-spongiform-encephalopathy-bse.html" rel="noopener noreferrer" target="_blank"><span style="color: #cc6611;"></span></a><span style="color: #cc6611;"><a href="http://bovineprp.blogspot.com/2016/07/bovine-spongiform-encephalopathy-bse.html" target="_blank">http://bovineprp.blogspot.com/2016/07/bovine-spongiform-encephalopathy-bse.html</a></span></span></span></span></div>
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<span style="color: black; font-size: 12pt; margin: 0px;"><span style="color: black; font-family: "Arial",sans-serif; font-size: 10pt; margin: 0px;"><br /><br /> Tuesday, July 26, 2016 <br /><br /> Atypical Bovine Spongiform Encephalopathy BSE TSE Prion UPDATE JULY 2016 <br /><br /><a href="http://bse-atypical.blogspot.com/2016/07/atypical-bovine-spongiform.html" rel="noopener noreferrer" target="_blank"><span style="color: blue;"></span></a><span style="color: blue;"><a href="http://bse-atypical.blogspot.com/2016/07/atypical-bovine-spongiform.html" rel="noopener noreferrer" target="_blank"><span style="color: #cc6611;"></span></a><span style="color: #cc6611;"><a href="http://bse-atypical.blogspot.com/2016/07/atypical-bovine-spongiform.html" target="_blank">http://bse-atypical.blogspot.com/2016/07/atypical-bovine-spongiform.html</a></span></span><br /> </span></span></div>
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<span style="color: black; font-size: 12pt; margin: 0px;"><span style="color: black; font-family: "Arial",sans-serif; font-size: 10pt; margin: 0px;">*** Calling Canadian beef unsafe is like calling your twin sister ugly," Dopp said.<br /><br /> Thursday, August 25, 2016 <br /><br /> *** FSIS Green Bay Dressed Beef Recalls Beef Products Due To Possible Specified Risk Materials Contamination the most high risk materials for BSE TSE PRION AKA MAD COW TYPE DISEASE ***<br /><br /><a href="http://specifiedriskmaterial.blogspot.com/2016/08/fsis-green-bay-dressed-beef-recalls.html" rel="noopener noreferrer" target="_blank">http://specifiedriskmaterial.blogspot.com/2016/08/fsis-green-bay-dressed-beef-recalls.html</a></span></span></div>
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<span style="color: black; font-size: 12pt; margin: 0px;"><span style="color: black; font-family: "Arial",sans-serif; font-size: 10pt; margin: 0px;"><br /><br /> Tuesday, August 9, 2016 <br /><br /> *** Concurrence with OIE Risk Designations for Bovine Spongiform Encephalopathy [Docket No. APHIS-2015-0055] <br /><br /><a href="http://bovineprp.blogspot.com/2016/08/concurrence-with-oie-risk-designations.html" rel="noopener noreferrer" target="_blank">http://bovineprp.blogspot.com/2016/08/concurrence-with-oie-risk-designations.html</a></span></span></div>
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<span style="color: black; font-size: 12pt; margin: 0px;"><span style="color: black; font-family: "Arial",sans-serif; font-size: 10pt; margin: 0px;">Monday, May 02, 2016<br /> <br /> *** Zoonotic Potential of CWD Prions: An Update Prion 2016 Tokyo ***<br /> <br /><a href="http://chronic-wasting-disease.blogspot.com/2016/05/zoonotic-potential-of-cwd-prions-update.html" rel="noopener noreferrer" target="_blank">http://chronic-wasting-disease.blogspot.com/2016/05/zoonotic-potential-of-cwd-prions-update.html</a><br /> <br /><a href="http://www.tandfonline.com/doi/abs/10.1080/19336896.2016.1163048?journalCode=kprn20" rel="noopener noreferrer" target="_blank">http://www.tandfonline.com/doi/abs/10.1080/19336896.2016.1163048?journalCode=kprn20</a><br /> </span></span></div>
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<span style="color: black; font-size: 12pt; margin: 0px;"><span style="color: black; font-family: "Arial",sans-serif; font-size: 10pt; margin: 0px;"><br /> why do we not want to do TSE transmission studies on chimpanzees $<br /> <br /> 5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man. I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough. Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis. <br /> <br /> snip... <br /> <br /> R. BRADLEY<br /> <br /><a href="http://collections.europarchive.org/tna/20080102222950/http://www.bseinquiry.gov.uk/files/yb/1990/09/23001001.pdf" rel="noopener noreferrer" target="_blank">http://collections.europarchive.org/tna/20080102222950/http://www.bseinquiry.gov.uk/files/yb/1990/09/23001001.pdf</a><br /> <br /> <br /><a href="http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=313160" rel="noopener noreferrer" target="_blank">http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=313160</a><br /> <br /> <br /> SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016<br /> <br /> Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl 1933-690X online</span></span></div>
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<br /><br /><a href="http://scrapie-usa.blogspot.com/2016/04/scrapie-ws-01-prion-diseases-in-animals.html" rel="noopener noreferrer" target="_blank">http://scrapie-usa.blogspot.com/2016/04/scrapie-ws-01-prion-diseases-in-animals.html</a></div>
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<br /> *** In complement to the recent demonstration that humanized mice are susceptible to scrapie, we report here the first observation of direct transmission of a natural classical scrapie isolate to a macaque after a 10-year incubation period. Neuropathologic examination revealed all of the features of a prion disease: spongiform change, neuronal loss, and accumulation of PrPres throughout the CNS. <br /> <br /> *** This observation strengthens the questioning of the harmlessness of scrapie to humans, at a time when protective measures for human and animal health are being dismantled and reduced as c-BSE is considered controlled and being eradicated. <br /> <br /> *** Our results underscore the importance of precautionary and protective measures and the necessity for long-term experimental transmission studies to assess the zoonotic potential of other animal prion strains. <br /> <br /> <a href="http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=313160" rel="noopener noreferrer" target="_blank">http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=313160</a><br /> <br /> <br /> O.05: Transmission of prions to primates after extended silent incubation periods: Implications for BSE and scrapie risk assessment in human populations <br /> <br /> Emmanuel Comoy, Jacqueline Mikol, Valerie Durand, Sophie Luccantoni, Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys Atomic Energy Commission; Fontenay-aux-Roses, France <br /> <br /> Prion diseases (PD) are the unique neurodegenerative proteinopathies reputed to be transmissible under field conditions since decades. The transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that an animal PD might be zoonotic under appropriate conditions. Contrarily, in the absence of obvious (epidemiological or experimental) elements supporting a transmission or genetic predispositions, PD, like the other proteinopathies, are reputed to occur spontaneously (atpical animal prion strains, sporadic CJD summing 80% of human prion cases). Non-human primate models provided the first evidences supporting the transmissibiity of human prion strains and the zoonotic potential of BSE. Among them, cynomolgus macaques brought major information for BSE risk assessment for human health (Chen, 2014), according to their phylogenetic proximity to humans and extended lifetime. We used this model to assess the zoonotic potential of other animal PD from bovine, ovine and cervid origins even after very long silent incubation periods. <br /> <br /> *** We recently observed the direct transmission of a natural classical scrapie isolate to macaque after a 10-year silent incubation period, <br /> <br /> ***with features similar to some reported for human cases of sporadic CJD, albeit requiring fourfold long incubation than BSE. Scrapie, as recently evoked in humanized mice (Cassard, 2014), <br /> <br /> ***is the third potentially zoonotic PD (with BSE and L-type BSE), <br /> <br /> ***thus questioning the origin of human sporadic cases. We will present an updated panorama of our different transmission studies and discuss the implications of such extended incubation periods on risk assessment of animal PD for human health. <br /> <br /> ===============<br /> <br /> ***thus questioning the origin of human sporadic cases*** <br /> <br /> ***our findings suggest that possible transmission risk of H-type BSE to sheep and human. Bioassay will be required to determine whether the PMCA products are infectious to these animals.<br /> <br /><a href="https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf" rel="noopener noreferrer" target="_blank">https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf</a><br /> </div>
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<span style="color: black; font-size: 12pt; margin: 0px;"><br /> Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA<br /><br /> Diagnosis and Reporting of Creutzfeldt-Jakob Disease<br /><br /> To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.<br /><br /> Terry S. Singeltary, Sr Bacliff, Tex<br /><br /> 1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.<br /><br /><a href="http://jama.jamanetwork.com/article.aspx?articleid=1031186" rel="noopener noreferrer" target="_blank"><span style="color: blue; font-family: Calibri;"></span></a><span style="color: blue; font-family: Calibri;"><a href="http://jama.jamanetwork.com/article.aspx?articleid=1031186" rel="noopener noreferrer" target="_blank"><span style="color: #cc6611;"></span></a><span style="color: #cc6611;"><a href="http://jama.jamanetwork.com/article.aspx?articleid=1031186" target="_blank">http://jama.jamanetwork.com/article.aspx?articleid=1031186</a></span></span> </span></div>
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<span style="color: black; font-size: 12pt; margin: 0px;"><span style="font-family: Times New Roman;"><br /></span> 26 March 2003 <br /><br /> Terry S. Singeltary, retired (medically) CJD WATCH <br /><br /> I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc? <br /><br /><a href="http://www.neurology.org/content/60/2/176/reply#neurology_el_535" rel="noopener noreferrer" target="_blank"><span style="color: blue; font-family: Calibri;"></span></a><span style="color: blue; font-family: Calibri;"><a href="http://www.neurology.org/content/60/2/176/reply#neurology_el_535" rel="noopener noreferrer" target="_blank"><span style="color: #cc6611;"></span></a><span style="color: #cc6611;"><a href="http://www.neurology.org/content/60/2/176/reply#neurology_el_535" target="_blank">http://www.neurology.org/content/60/2/176/reply#neurology_el_535</a></span></span> <br /><br /> Sent: Monday, January 08,2001 3:03 PM<br /><br /> TO: <a href="https://www.blogger.com/null" rel="noopener noreferrer" target="_blank"><span style="color: #cc6611;"></span></a><span style="color: #cc6611;"><a href="https://www.blogger.com/null">freas@CBS5055530.CBER.FDA.GOV</a></span><br /><u><span style="color: #cc6611;"><br /></span></u> FDA CJD BSE TSE Prion Scientific Advisors and Consultants Staff January 2001 Meeting Singeltary Submission<br /><br /> 2001 FDA CJD TSE Prion Singeltary Submission <br /><br /><a href="http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf" rel="noopener noreferrer" target="_blank"><span style="color: blue; font-family: Calibri;"></span></a><span style="color: blue; font-family: Calibri;"><a href="http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf" rel="noopener noreferrer" target="_blank"><span style="color: #cc6611;"></span></a><span style="color: #cc6611;"><a href="http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf" target="_blank">http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf</a></span></span> <br /><br /> 2 January 2000 <br /><br /> British Medical Journal <br /><br /> U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well <br /><br /><a href="http://www.bmj.com/rapid-response/2011/10/28/us-scientist-should-be-concerned-cjd-epidemic-us-well" rel="noopener noreferrer" target="_blank"><span style="color: blue; font-family: Calibri;"></span></a><span style="color: blue; font-family: Calibri;"><a href="http://www.bmj.com/rapid-response/2011/10/28/us-scientist-should-be-concerned-cjd-epidemic-us-well" rel="noopener noreferrer" target="_blank"><span style="color: #cc6611;"></span></a><span style="color: #cc6611;"><a href="http://www.bmj.com/rapid-response/2011/10/28/us-scientist-should-be-concerned-cjd-epidemic-us-well" target="_blank">http://www.bmj.com/rapid-response/2011/10/28/us-scientist-should-be-concerned-cjd-epidemic-us-well</a></span></span> <br /><br /> 15 November 1999 <br /><br /> British Medical Journal <br /><br /> vCJD in the USA * BSE in U.S. <br /><br /><a href="http://www.bmj.com/rapid-response/2011/10/28/re-vcjd-usa-bse-us " rel="noopener noreferrer" target="_blank"><span style="color: blue; font-family: Calibri;"></span></a><span style="color: blue; font-family: Calibri;"><a href="http://www.bmj.com/rapid-response/2011/10/28/re-vcjd-usa-bse-us " rel="noopener noreferrer" target="_blank"><span style="color: #cc6611;"></span></a><span style="color: #cc6611;"><a href="http://www.bmj.com/rapid-response/2011/10/28/re-vcjd-usa-bse-us " target="_blank">http://www.bmj.com/rapid-response/2011/10/28/re-vcjd-usa-bse-us </a>;</span>;</span>;</span></div>
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Prion Institute protein folding and misfolding; pathobiology of TSEs; surveillance, control; and TSEs </h3>
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Heidenhain variant of Creutzfeldt–Jakob disease in a patient who had bovine bioprosthetic valve implantation </h3>
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<span style="margin: 0px;"><span style="font-family: Calibri;">Year : 2016 | Volume : 64 | Issue : 10 | Page : 767-769 <span style="font-family: Arial, Helvetica, sans-serif;"></span></span></span></div>
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<span style="color: black; font-size: 12pt; margin: 0px;">Transmissibility of Gerstmann–Sträussler–Scheinker syndrome in rodent models: new insights into the molecular underpinnings of prion infectivity</span></div>
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<span style="color: blue; font-size: 12pt; margin: 0px;"><a href="http://transmissiblespongiformencephalopathy.blogspot.com/2016/11/transmissibility-of-gerstmannstraussler.html" rel="noopener noreferrer" target="_blank"><span style="color: blue; font-family: Calibri;"></span></a><span style="color: blue; font-family: Calibri;"><a href="http://transmissiblespongiformencephalopathy.blogspot.com/2016/11/transmissibility-of-gerstmannstraussler.html" target="_blank"><span style="color: #cc6611;">http://transmissiblespongiformencephalopathy.blogspot.com/2016/11/transmissibility-of-gerstmannstraussler.html</span></a></span></span></div>
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<span style="color: black; font-family: "Arial",sans-serif; font-size: 12pt; margin: 0px;">Terry S. Singeltary Sr. </span></div>
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<span style="color: black; font-family: "Arial",sans-serif; font-size: 12pt; margin: 0px;"><<a href="https://www.blogger.com/null" rel="noopener noreferrer" target="_blank"><span style="color: #cc6611;"></span></a><span style="color: #cc6611;"><a href="https://www.blogger.com/null">flounder9@verizon.net</a></span>></span></div>
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</span><b></b><i></i><u></u><sub></sub><sup></sup><strike></strike><br />Terry S. Singeltary Sr.http://www.blogger.com/profile/06986622967539963260noreply@blogger.com0tag:blogger.com,1999:blog-6491423064023155264.post-42826925289400459092014-11-27T12:17:00.002-06:002014-11-27T12:17:17.791-06:00Animal models of tauopathies and their implications for research/translation into the clinic<div>
Invited Review</div>
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Animal models of tauopathies and their implications for
research/translation into the clinic </div>
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Simon Dujardin, Morvane Colin* and Luc Buée DOI: 10.1111/nan.12200 </div>
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Author Information</div>
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Inserm, UMR1172 Jean-Pierre Aubert research centre, Lille, France ;
Université de Lille, Faculté de Médecine, Lille, France; CHRU, Memory Clinic,
Lille, France </div>
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* Corresponding authors: Drs L. Buée & M. Colin Inserm UMR1172,
‘Alzheimer & Tauopathies’ Bâtiment Biserte, rue Polonovski 59045 Lille
Cedex, France Tel: +33 320 298850, Fax: +33 220 538562 Emails:
morvane.colin@inserm.fr, luc.buee@inserm.fr </div>
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<div>
This article has been accepted for publication and undergone full peer
review but has not been through the copyediting, typesetting, pagination and
proofreading process, which may lead to differences between this version and the
Version of Record. Please cite this article as doi: 10.1111/nan.12200 </div>
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Publication History Accepted manuscript online: 26 NOV 2014 10:37PM EST
Manuscript Accepted: 23 NOV 2014 </div>
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Keywords:</div>
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Alzheimer's disease; prion; propagation; tau protein; phosphorylation;
aggregation; neurodegeneration; therapeutic approaches </div>
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Abstract </div>
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Our aims are to review animal models of tauopathies, which include a number
of brain disorders with various aetiologies, including aging, genetics,
infectious diseases, toxins, trauma, and other unknown factors. Tauopathies are
characterised by the accumulation of filaments of the microtubule-associated tau
protein. The different aetiopathogeneses and distinct molecular events involved
in tau aggregation have led to the development of various animal models for
these diseases. </div>
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In this review, rather than listing all current models, we focus on
specific animal models addressing, among others, the question of tau
hyperphosphorylation, tau aggregation and tau spreading. Physiological
conditions, including normal aging and hibernation, may exhibit tau
phosphorylation and some aspects of tauopathies. However, most of the models of
tauopathies involve genetically modified animals (mostly rodents, but also fruit
fly, zebrafish, and worm). Some of these models have been crucial for the
development of therapeutic approaches in humans. </div>
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The present review shows the difficulty in pinpointing a specific mechanism
that may be targeted in tauopathies but also opens up new avenues for innovative
therapeutic strategies. </div>
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<a href="http://onlinelibrary.wiley.com/doi/10.1111/nan.12200/abstract?campaign=wolacceptedarticle">http://onlinelibrary.wiley.com/doi/10.1111/nan.12200/abstract?campaign=wolacceptedarticle</a>
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Monday, November 17, 2014 </div>
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Prion-like transmission and spreading of tau pathology </div>
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<a href="http://tauopathies.blogspot.com/2014/11/prion-like-transmission-and-spreading.html">http://tauopathies.blogspot.com/2014/11/prion-like-transmission-and-spreading.html</a>
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Wednesday, June 19, 2013 </div>
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</div>
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Spreading of tau pathology in Alzheimer's disease by cell-to-cell
transmission </div>
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</div>
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<a href="http://tauopathies.blogspot.com/2013/06/spreading-of-tau-pathology-in.html">http://tauopathies.blogspot.com/2013/06/spreading-of-tau-pathology-in.html</a>
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Saturday, May 25, 2013</div>
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</div>
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Brain homogenates from human tauopathies induce tau inclusions in mouse
brain</div>
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<a href="http://tauopathies.blogspot.com/2013/05/brain-homogenates-from-human.html">http://tauopathies.blogspot.com/2013/05/brain-homogenates-from-human.html</a>
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<a href="http://tauopathies.blogspot.com/">http://tauopathies.blogspot.com/</a>
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Sunday, November 23, 2014 </div>
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Transmission Characteristics of Variably Protease-Sensitive Prionopathy
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* We concluded that VPSPr is transmissible; thus, it is an authentic prion
disease.</div>
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<a href="http://vpspr.blogspot.com/2014/11/transmission-characteristics-of.html">http://vpspr.blogspot.com/2014/11/transmission-characteristics-of.html</a></div>
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<a href="http://vpspr.blogspot.com/">http://vpspr.blogspot.com/</a></div>
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<a href="http://prionopathy.blogspot.com/">http://prionopathy.blogspot.com/</a></div>
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<a href="http://transmissiblespongiformencephalopathy.blogspot.com/">http://transmissiblespongiformencephalopathy.blogspot.com/</a>
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Self-Propagative Replication of Ab Oligomers Suggests Potential
Transmissibility in Alzheimer Disease</div>
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Received July 24, 2014; Accepted September 16, 2014; Published November 3,
2014</div>
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<a href="http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0111492&representation=PDF">http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0111492&representation=PDF</a>
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Singeltary comment ;</div>
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<a href="http://www.plosone.org/annotation/listThread.action?root=82860">http://www.plosone.org/annotation/listThread.action?root=82860</a>
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Monday, November 3, 2014</div>
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USA CJD TSE PRION UNIT, TEXAS, SURVEILLANCE UPDATE NOVEMBER 2014 </div>
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National Prion Disease Pathology Surveillance Center Cases Examined1
(October 7, 2014) </div>
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***6 Includes 11 cases in which the diagnosis is pending, and 19
inconclusive cases; </div>
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***7 Includes 12 (11 from 2014) cases with type determination pending in
which the diagnosis of vCJD has been excluded. </div>
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***The sporadic cases include 2660 cases of sporadic Creutzfeldt-Jakob
disease (sCJD), </div>
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***50 cases of Variably Protease-Sensitive Prionopathy (VPSPr) </div>
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***and 21 cases of sporadic Fatal Insomnia (sFI). </div>
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<a href="http://prionunitusaupdate.blogspot.com/2014/11/usa-cjd-tse-prion-unit-texas.html">http://prionunitusaupdate.blogspot.com/2014/11/usa-cjd-tse-prion-unit-texas.html</a>
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Sunday, November 23, 2014 </div>
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Confirmed Variant Creutzfeldt-Jakob Disease (variant CJD) Case in Texas in
June 2014 confirmed as USA case NOT European </div>
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<a href="http://vcjd.blogspot.com/2014/11/confirmed-variant-creutzfeldt-jakob.html">http://vcjd.blogspot.com/2014/11/confirmed-variant-creutzfeldt-jakob.html</a> </div>
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TSS
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Terry S. Singeltary Sr.http://www.blogger.com/profile/06986622967539963260noreply@blogger.com0tag:blogger.com,1999:blog-6491423064023155264.post-18898686023211522302014-11-17T11:00:00.002-06:002014-11-17T11:00:33.997-06:00Prion-like transmission and spreading of tau pathology<div>
Invited Review</div>
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Prion-like transmission and spreading of tau pathology Florence
Clavaguera1, Jürgen Hench1, Michel Goedert2 and Markus Tolnay1,* DOI:
10.1111/nan.12197<br />
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This article is protected by copyright. All rights reserved. <br />
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Additional Information(Hide All) Author InformationPublication History
Author Information 1 Institute of Pathology, University Hospital Basel,
Schönbeinstrasse 40, CH-4031 Basel, Switzerland 2 MRC Laboratory of Molecular
Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK * Please send
correspondence to Markus Tolnay at the above address. Email:
markus.tolnay@usb.ch <br />
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<div>
</div>
This article has been accepted for publication and undergone full peer
review but has not been through the copyediting, typesetting, pagination and
proofreading process, which may lead to differences between this version and the
Version of Record. Please cite this article as doi: 10.1111/nan.12197 <br />
<br />
<div>
</div>
Publication History Accepted manuscript online: 17 NOV 2014 01:23AM EST
Manuscript Accepted: 13 NOV 2014<br />
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Abstract<br />
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</div>
Filaments made of hyperphosphorylated tau protein are encountered in a
number of neurodegenerative diseases referred to as “tauopathies”. In the most
prevalent tauopathy, Alzheimer's disease, tau pathology progresses in a
stereotypical manner with the first lesions appearing in the locus coeruleus and
the entorhinal cortex from where they appear to spread to the hippocampus and
neocortex. Propagation of tau pathology is also characteristic of argyrophilic
grain disease, where the tau lesions appear to spread throughout distinct
regions of the limbic system. These findings strongly implicate neuron-to-neuron
propagation of tau aggregates. Isoform composition and morphology of tau
filaments can differ between tauopathies suggesting the existence of
conformationally diverse tau strains. ***Altogether, this points to prion-like
mechanisms in the pathogenesis of tauopathies. <br />
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<a href="http://onlinelibrary.wiley.com/doi/10.1111/nan.12197/abstract?campaign=wolacceptedarticle">http://onlinelibrary.wiley.com/doi/10.1111/nan.12197/abstract?campaign=wolacceptedarticle</a>
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<div>
</div>
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<div>
Self-Propagative Replication of Ab Oligomers Suggests Potential
Transmissibility in Alzheimer Disease</div>
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</div>
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<div>
Received July 24, 2014; Accepted September 16, 2014; Published November 3,
2014</div>
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<a href="http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0111492&representation=PDF">http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0111492&representation=PDF</a>
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Singeltary comment ;</div>
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<a href="http://www.plosone.org/annotation/listThread.action?root=82860">http://www.plosone.org/annotation/listThread.action?root=82860</a>
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Wednesday, June 19, 2013 </div>
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</div>
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Spreading of tau pathology in Alzheimer's disease by cell-to-cell
transmission </div>
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</div>
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<a href="http://tauopathies.blogspot.com/2013/06/spreading-of-tau-pathology-in.html">http://tauopathies.blogspot.com/2013/06/spreading-of-tau-pathology-in.html</a></div>
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Saturday, May 25, 2013</div>
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</div>
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<div>
Brain homogenates from human tauopathies induce tau inclusions in mouse
brain</div>
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</div>
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<a href="http://tauopathies.blogspot.com/2013/05/brain-homogenates-from-human.html">http://tauopathies.blogspot.com/2013/05/brain-homogenates-from-human.html</a>
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<a href="http://prionopathy.blogspot.com/" title="http://prionopathy.blogspot.com/">http://prionopathy.blogspot.com/</a></div>
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<a href="http://proteinopathies.blogspot.com/" title="http://proteinopathies.blogspot.com/">http://proteinopathies.blogspot.com/</a></div>
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<a href="http://earlyonsetdementia.blogspot.com/" title="http://earlyonsetdementia.blogspot.com/">http://earlyonsetdementia.blogspot.com/</a></div>
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Tuesday, November 04, 2014 </div>
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</div>
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Towards an Age-Dependent Transmission Model of Acquired and Sporadic
Creutzfeldt-Jakob Disease</div>
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<a href="http://creutzfeldt-jakob-disease.blogspot.com/2014/11/towards-age-dependent-transmission.html">http://creutzfeldt-jakob-disease.blogspot.com/2014/11/towards-age-dependent-transmission.html</a></div>
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<a href="http://creutzfeldt-jakob-disease.blogspot.com/" style="href: "http://creutzfeldt-jakob-disease.blogspot.com/2014/11/towards-age-dependent-transmission.html";">http://creutzfeldt-jakob-disease.blogspot.com/</a></div>
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Friday, January 10, 2014 </div>
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vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type
prion disease, what it ??? </div>
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<a href="http://transmissiblespongiformencephalopathy.blogspot.com/2014/01/vpspr-sgss-sffi-tse-iatrogenic-by.html">http://transmissiblespongiformencephalopathy.blogspot.com/2014/01/vpspr-sgss-sffi-tse-iatrogenic-by.html</a>
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<a href="http://transmissiblespongiformencephalopathy.blogspot.com/" style="href: "http://transmissiblespongiformencephalopathy.blogspot.com/2014/01/vpspr-sgss-sffi-tse-iatrogenic-by.html";">http://transmissiblespongiformencephalopathy.blogspot.com/</a></div>
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Monday, November 3, 2014</div>
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USA CJD TSE PRION UNIT, TEXAS, SURVEILLANCE UPDATE NOVEMBER 2014 </div>
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</div>
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National Prion Disease Pathology Surveillance Center Cases Examined1
(October 7, 2014) </div>
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</div>
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***6 Includes 11 cases in which the diagnosis is pending, and 19
inconclusive cases; </div>
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</div>
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***7 Includes 12 (11 from 2014) cases with type determination pending in
which the diagnosis of vCJD has been excluded. </div>
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***The sporadic cases include 2660 cases of sporadic Creutzfeldt-Jakob
disease (sCJD), </div>
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***50 cases of Variably Protease-Sensitive Prionopathy (VPSPr) </div>
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***and 21 cases of sporadic Fatal Insomnia (sFI). </div>
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<div>
<a href="http://prionunitusaupdate.blogspot.com/2014/11/usa-cjd-tse-prion-unit-texas.html">http://prionunitusaupdate.blogspot.com/2014/11/usa-cjd-tse-prion-unit-texas.html</a>
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</div>
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<div>
<a href="http://prionunitusaupdate.blogspot.com/" style="href: "http://prionunitusaupdate.blogspot.com/2014/11/usa-cjd-tse-prion-unit-texas.html";">http://prionunitusaupdate.blogspot.com/</a></div>
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TSS </div>
Terry S. Singeltary Sr.http://www.blogger.com/profile/06986622967539963260noreply@blogger.com0tag:blogger.com,1999:blog-6491423064023155264.post-84893322354439484082013-06-19T16:57:00.001-05:002013-06-19T16:57:12.647-05:00Spreading of tau pathology in Alzheimer's disease by cell-to-cell transmission<div>
Spreading of tau pathology in Alzheimer's disease by cell-to-cell
transmission </div>
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Nguyen-Vi Mohamed, Thibaut Herrou, Vanessa Plouffe, Nicolas Piperno,
Nicole Leclerc*</div>
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Article first published online: 16 JUN 2013</div>
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DOI: 10.1111/ejn.12229</div>
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© 2013 Federation of European Neuroscience Societies and John Wiley &
Sons Ltd </div>
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Keywords:</div>
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Alzheimer's disease; endocytosis and secretion; propagation; tau </div>
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Abstract </div>
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It is well documented that neurofibrillary tangles composed of aggregated
tau protein propagate in a predictable pattern in Alzheimer's disease (AD). The
mechanisms underlying the propagation of tau pathology are still poorly
understood. Recent studies have provided solid data demonstrating that in
several neurodegenerative diseases including AD, the spreading of misfolded
protein aggregates in the brain would result from prion-like cell-to-cell
transmission. Consistent with this new concept, recent studies have reported
that human tau can be released in the extracellular space by an active process
of secretion, and can be endocytosed both in vitro and in vivo. Most
importantly, it was reported that the spreading of tau pathology was observed
along synaptically connected circuits in a transgenic mouse model where human
tau overexpression was restricted in the entorhinal cortex. This indicates that
secretion of tau by presynaptic neurons and its uptake by postsynaptic neurons
could be the sequential events leading to the propagation of tau pathology in
the brain. </div>
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<div>
<a href="http://onlinelibrary.wiley.com/doi/10.1111/ejn.12229/abstract;jsessionid=B59529A1F791559054F0CE22EB4AD227.d04t02">http://onlinelibrary.wiley.com/doi/10.1111/ejn.12229/abstract;jsessionid=B59529A1F791559054F0CE22EB4AD227.d04t02</a>
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Published online before print May 20, 2013, doi: 10.1073/pnas.1301175110
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PNAS May 20, 2013 </div>
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Brain homogenates from human tauopathies induce tau inclusions in mouse
brain </div>
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<div>
Florence Clavagueraa, Hiroyasu Akatsub, Graham Fraserc, R. Anthony
Crowtherc, Stephan Franka, Jürgen Hencha, Alphonse Probsta, David T. Winklera,d,
Julia Reichwalde, Matthias Staufenbiele, Bernardino Ghettif, Michel
Goedertc,1,2, and Markus Tolnaya,1,2 </div>
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<div>
aDepartment of Neuropathology, Institute of Pathology, University Hospital,
4031 Basel, Switzerland; bChoju Medical Institute, Fukushimura Hospital,
Toyohashi City 441-8124, Japan; cMedical Research Council Laboratory of
Molecular Biology, Cambridge CB2 0QH, United Kingdom; dDepartment of Neurology,
University Hospital, 4031 Basel, Switzerland; eNovartis Institutes for
Biomedical Research, 4056 Basel, Switzerland; and fIndiana Alzheimer Disease
Center and Department of Pathology and Laboratory Medicine, Indiana University,
Indianapolis, IN 46202 </div>
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<div>
Edited by Anders Bjorklund, Lund University, Lund, Sweden, and approved
April 25, 2013 (received for review January 18, 2013) </div>
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</div>
<div>
Filamentous inclusions made of hyperphosphorylated tau are characteristic
of numerous human neurodegenerative diseases, including Alzheimer’s disease,
tangle-only dementia, Pick disease, argyrophilic grain disease (AGD),
progressive supranuclear palsy, and corticobasal degeneration. In Alzheimer’s
disease and AGD, it has been shown that filamentous tau appears to spread in a
stereotypic manner as the disease progresses. We previously demonstrated that
the injection of brain extracts from human mutant P301S tau-expressing
transgenic mice into the brains of mice transgenic for wild-type human tau (line
ALZ17) resulted in the assembly of wild-type human tau into filaments and the
spreading of tau inclusions from the injection sites to anatomically connected
brain regions. Here we injected brain extracts from humans who had died with
various tauopathies into the hippocampus and cerebral cortex of ALZ17 mice.
Argyrophilic tau inclusions formed in all cases and following the injection of
the corresponding brain extracts, we recapitulated the hallmark lesions of AGD,
PSP and CBD. Similar inclusions also formed after intracerebral injection of
brain homogenates from human tauopathies into nontransgenic mice. Moreover, the
induced formation of tau aggregates could be propagated between mouse brains.
These findings suggest that once tau aggregates have formed in discrete brain
areas, they become self-propagating and spread in a prion-like manner. </div>
<br />
<div>
</div>
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</div>
<div>
</div>
<div>
snip... </div>
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<div>
</div>
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<div>
</div>
<div>
</div>
<div>
The present work indicates that once small numbers of tau inclusions have
formed in the brain, they may become selfpropagating and spread in a prion-like
manner, independently of other pathogenic mechanisms. What is true of aggregated
human tau may also be the case of other aggregation-prone proteins that cause
human neurodegenerative diseases, including α-synuclein, superoxide dismutase 1,
huntingtin, trans-activator regulatory (TAR) DNA-binding protein 43 (TDP-43),
and Aβ (47). The inhibition of cell-to-cell transmission of pathological
aggregates, for instance by passive immunotherapy, may constitute an effective
mechanism-based therapeutic strategy for most human neurodegenerative diseases.
</div>
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</div>
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</div>
<div>
</div>
<div>
<a href="http://www.pnas.org/content/early/2013/05/17/1301175110.full.pdf+html">http://www.pnas.org/content/early/2013/05/17/1301175110.full.pdf+html</a>
</div>
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<div>
</div>
<div>
Tuesday, May 21, 2013 </div>
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<div>
</div>
<br />
<div>
IS ALZHEIMER’S DISEASE A PRION DISEASE? the possible secondary transmission
by blood transfusion are posed </div>
<br />
<div>
</div>
<br />
<div>
<a href="http://betaamyloidcjd.blogspot.com/2013/05/is-alzheimers-disease-prion-disease.html">http://betaamyloidcjd.blogspot.com/2013/05/is-alzheimers-disease-prion-disease.html</a>
</div>
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</div>
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</div>
<div>
Tuesday, May 7, 2013 </div>
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<div>
</div>
<br />
<div>
Proteinopathies, a core concept for understanding and ultimately treating
degenerative disorders? </div>
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<div>
</div>
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<div>
<a href="http://proteinopathies.blogspot.com/2013/05/proteinopathies-core-concept-for.html">http://proteinopathies.blogspot.com/2013/05/proteinopathies-core-concept-for.html</a>
</div>
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</div>
<div>
Wednesday, May 16, 2012 </div>
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</div>
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</div>
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</div>
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<div>
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion
disease, Iatrogenic, what if ? </div>
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<div>
</div>
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<div>
Background </div>
<br />
<div>
</div>
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<div>
Alzheimer’s disease and Transmissible Spongiform Encephalopathy disease
have both been around a long time, and was discovered in or around the same time
frame, early 1900’s. Both diseases are incurable and debilitating brain disease,
that are in the end, 100% fatal, with the incubation/clinical period of the
Alzheimer’s disease being longer (most of the time) than the TSE prion disease.
Symptoms are very similar, and pathology is very similar. </div>
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<div>
</div>
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<div>
Methods </div>
<br />
<div>
</div>
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<div>
Through years of research, as a layperson, of peer review journals,
transmission studies, and observations of loved ones and friends that have died
from both Alzheimer’s and the TSE prion disease i.e. Heidenhain Variant
Creutzfelt Jakob Disease CJD. </div>
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<div>
</div>
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<div>
Results </div>
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<div>
</div>
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<div>
I propose that Alzheimer’s is a TSE disease of low dose, slow, and long
incubation disease, and that Alzheimer’s is Transmissible, and is a threat to
the public via the many Iatrogenic routes and sources. It was said long ago that
the only thing that disputes this, is Alzheimer’s disease transmissibility, or
the lack of. The likelihood of many victims of Alzheimer’s disease from the many
different Iatrogenic routes and modes of transmission as with the TSE prion
disease. </div>
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<div>
</div>
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<div>
Conclusions </div>
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<div>
</div>
<br />
<div>
There should be a Global Congressional Science round table event set up
immediately to address these concerns from the many potential routes and sources
of the TSE prion disease, including Alzheimer’s disease, and a emergency global
doctrine put into effect to help combat the spread of Alzheimer’s disease via
the medical, surgical, dental, tissue, and blood arena’s. All human and animal
TSE prion disease, including Alzheimer’s should be made reportable in every
state, and Internationally, WITH NO age restrictions. Until a proven method of
decontamination and autoclaving is proven, and put forth in use universally, in
all hospitals and medical, surgical arena’s, or the TSE prion agent will
continue to spread. IF we wait until science and corporate politicians wait
until politics lets science _prove_ this once and for all, and set forth
regulations there from, we will all be exposed to the TSE Prion agents, if that
has not happened already. </div>
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<div>
</div>
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<div>
end...tss </div>
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</div>
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<div>
</div>
<div>
SEE FULL TEXT AND SOURCE REFERENCES ; </div>
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</div>
<div>
</div>
<div>
Wednesday, May 16, 2012 </div>
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<div>
</div>
<br />
<div>
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion
disease, Iatrogenic, what if ? </div>
<br />
<div>
</div>
<br />
<div>
Proposal ID: 29403 </div>
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<div>
</div>
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<div>
<a href="http://betaamyloidcjd.blogspot.com/2012/05/alzheimers-disease-and-transmissible.html">http://betaamyloidcjd.blogspot.com/2012/05/alzheimers-disease-and-transmissible.html</a>
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</div>
<div>
Wednesday, September 21, 2011 </div>
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</div>
<br />
<div>
PrioNet Canada researchers in Vancouver confirm prion-like properties in
Amyotrophic Lateral Sclerosis (ALS) </div>
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<div>
</div>
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<div>
<a href="http://transmissiblespongiformencephalopathy.blogspot.com/2011/09/prionet-canada-researchers-in-vancouver.html">http://transmissiblespongiformencephalopathy.blogspot.com/2011/09/prionet-canada-researchers-in-vancouver.html</a>
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</div>
<div>
Sunday, February 10, 2013 </div>
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<div>
</div>
<br />
<div>
Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a
Prion-Like Disorder? </div>
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<div>
</div>
<br />
<div>
<a href="http://betaamyloidcjd.blogspot.com/2013/02/parkinsons-disease-and-alpha-synuclein.html">http://betaamyloidcjd.blogspot.com/2013/02/parkinsons-disease-and-alpha-synuclein.html</a>
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</div>
<div>
Ann N Y Acad Sci. 1982;396:131-43. </div>
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</div>
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</div>
<div>
Alzheimer's disease and transmissible virus dementia (Creutzfeldt-Jakob
disease). </div>
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</div>
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</div>
<div>
Brown P, Salazar AM, Gibbs CJ Jr, Gajdusek DC. </div>
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Abstract </div>
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</div>
<div>
Ample justification exists on clinical, pathologic, and biologic grounds
for considering a similar pathogenesis for AD and the spongiform virus
encephalopathies. However, the crux of the comparison rests squarely on results
of attempts to transmit AD to experimental animals, and these results have not
as yet validated a common etiology. Investigations of the biologic similarities
between AD and the spongiform virus encephalopathies proceed in several
laboratories, and our own observation of inoculated animals will be continued in
the hope that incubation periods for AD may be even longer than those of CJD.
</div>
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<div>
<a href="http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.1982.tb26849.x/abstract">http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.1982.tb26849.x/abstract</a>
</div>
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<div>
CJD1/9 0185 Ref: 1M51A </div>
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</div>
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<div>
IN STRICT CONFIDENCE </div>
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</div>
<br />
<div>
Dr McGovern From: Dr A Wight Date: 5 January 1993 Copies: Dr Metters Dr
Skinner Dr Pickles Dr Morris Mr Murray </div>
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</div>
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<div>
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES </div>
<br />
<div>
</div>
<br />
<div>
1. CMO will wish to be aware that a meeting was held at DH yesterday, 4
January, to discuss the above findings. It was chaired by Professor Murray
(Chairman of the MRC Co-ordinating Committee on Research in the Spongiform
Encephalopathies in Man), and attended by relevant experts in the fields of
Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the
spongiform encephalopathies, and by representatives of the MRC and AFRC. 2.
Briefly, the meeting agreed that: </div>
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<div>
</div>
<br />
<div>
i) Dr Ridley et als findings of experimental induction of p amyloid in
primates were valid, interesting and a significant advance in the understanding
of neurodegenerative disorders; </div>
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<div>
</div>
<br />
<div>
ii) there were no immediate implications for the public health, and no
further safeguards were thought to be necessary at present; and </div>
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<div>
</div>
<br />
<div>
iii) additional research was desirable, both epidemiological and at the
molecular level. Possible avenues are being followed up by DH and the MRC, but
the details will require further discussion. 93/01.05/4.1 </div>
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<div>
</div>
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<div>
<a href="http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf">http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf</a>
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</div>
<div>
BSE101/1 0136 </div>
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<div>
</div>
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<div>
IN CONFIDENCE </div>
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<div>
</div>
<br />
<div>
5 NOV 1992 CMO From: Dr J S Metters DCMO 4 November 1992 </div>
<br />
<div>
</div>
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<div>
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES </div>
<br />
<div>
</div>
<br />
<div>
1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have
recognized the public sensitivity of these findings and intend to report them in
their proper context. This hopefully will avoid misunderstanding and possible
distortion by the media to portray the results as having more greater
significance than the findings so far justify. </div>
<br />
<div>
</div>
<br />
<div>
2. Using a highly unusual route of transmission (intra-cerebral injection)
the researchers have demonstrated the transmission of a pathological process
from two cases one of severe Alzheimer's disease the other of
Gerstmann-Straussler disease to marmosets. However they have not demonstrated
the transmission of either clinical condition as the "animals were behaving
normally when killed'. As the report emphasizes the unanswered question is
whether the disease condition would have revealed itself if the marmosets had
lived longer. They are planning further research to see if the conditions, as
opposed to the partial pathological process, is transmissible. What are the
implications for public health? </div>
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<div>
</div>
<br />
<div>
3. The route of transmission is very specific and in the natural state of
things highly unusual. However it could be argued that the results reveal a
potential risk, in that brain tissue from these two patients has been shown to
transmit a pathological process. Should therefore brain tissue from such cases
be regarded as potentially infective? Pathologists, morticians, neuro surgeons
and those assisting at neuro surgical procedures and others coming into contact
with "raw" human brain tissue could in theory be at risk. However, on a priori
grounds given the highly specific route of transmission in these experiments
that risk must be negligible if the usual precautions for handling brain tissue
are observed. </div>
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<div>
</div>
<br />
<div>
92/11.4/1-1 BSE101/1 0137 </div>
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<div>
</div>
<br />
<div>
4. The other dimension to consider is the public reaction. To some extent
the GSS case demonstrates little more than the transmission of BSE to a pig by
intra-cerebral injection. If other prion diseases can be transmitted in this way
it is little surprise that some pathological findings observed in GSS were also
transmissible to a marmoset. But the transmission of features of Alzheimer's
pathology is a different matter, given the much greater frequency of this
disease and raises the unanswered question whether some cases are the result of
a transmissible prion. The only tenable public line will be that "more research
is required" before that hypothesis could be evaluated. The possibility on a
transmissible prion remains open. In the meantime MRC needs carefully to
consider the range and sequence of studies needed to follow through from the
preliminary observations in these two cases. Not a particularly comfortable
message, but until we know more about the causation of Alzheimer's disease the
total reassurance is not practical. </div>
<br />
<div>
</div>
<br />
<div>
JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832
121/YdeS 92/11.4/1.2 </div>
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<div>
</div>
<br />
<div>
<a href="http://collections.europarchive.org/tna/20080102232842/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf">http://collections.europarchive.org/tna/20080102232842/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf</a>
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</div>
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</div>
<div>
BSE101/1 0136 </div>
<br />
<div>
</div>
<br />
<div>
IN CONFIDENCE </div>
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<div>
</div>
<br />
<div>
CMO </div>
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<div>
</div>
<br />
<div>
From: Dr J S Metters DCMO </div>
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<div>
</div>
<br />
<div>
4 November 1992 </div>
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<div>
</div>
<br />
<div>
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES </div>
<br />
<div>
</div>
<br />
<div>
<a href="http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf">http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf</a>
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<div>
CJD1/9 0185 </div>
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<div>
</div>
<br />
<div>
Ref: 1M51A </div>
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<div>
</div>
<br />
<div>
IN STRICT CONFIDENCE </div>
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<div>
</div>
<br />
<div>
From: Dr. A Wight Date: 5 January 1993 </div>
<br />
<div>
</div>
<br />
<div>
Copies: </div>
<br />
<div>
</div>
<br />
<div>
Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray </div>
<br />
<div>
</div>
<br />
<div>
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES </div>
<br />
<div>
</div>
<br />
<div>
<a href="http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf">http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf</a>
</div>
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</div>
<div>
Wednesday, January 5, 2011 </div>
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<div>
</div>
<br />
<div>
ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011 Prions
</div>
<br />
<div>
</div>
<br />
<div>
David W. Colby1,* and Stanley B. Prusiner1,2 </div>
<br />
<div>
</div>
<br />
<div>
<a href="http://cshperspectives.cshlp.org/content/3/1/a006833.full.pdf+html">http://cshperspectives.cshlp.org/content/3/1/a006833.full.pdf+html</a>
</div>
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<div>
</div>
<br />
<div>
<a href="http://betaamyloidcjd.blogspot.com/2011/01/enlarging-spectrum-of-prion-like.html">http://betaamyloidcjd.blogspot.com/2011/01/enlarging-spectrum-of-prion-like.html</a>
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</div>
<div>
</div>
<div>
Friday, September 3, 2010</div>
<br />
<div>
</div>
<br />
<div>
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids,
Prionpathy, Prionopathy, TSE </div>
<br />
<div>
</div>
<br />
<div>
<a href="http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html">http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html</a>
</div>
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<div>
</div>
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<div>
<a href="http://betaamyloidcjd.blogspot.com/">http://betaamyloidcjd.blogspot.com/</a>
</div>
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</div>
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</div>
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<div>
SCENARIO 3: ‘THE THIN STEMMED GLASS’ </div>
<br />
<div>
</div>
<br />
<div>
... a TSE is found that is linked to Alzheimer’s disease. </div>
<br />
<div>
</div>
<br />
<div>
<a href="http://madcowtesting.blogspot.com/2012/12/canada-19-cases-of-mad-cow-disease.html">http://madcowtesting.blogspot.com/2012/12/canada-19-cases-of-mad-cow-disease.html</a>
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</div>
<div>
Thursday, January 17, 2013 </div>
<br />
<div>
</div>
<br />
<div>
TSE guidance, surgical, dental, blood risk factors, Part 4 Infection
control of CJD, vCJD and other human prion diseases in healthcare and community
settings (updated January 2013) </div>
<br />
<div>
</div>
<br />
<div>
<a href="http://transmissiblespongiformencephalopathy.blogspot.com/2013/01/tse-guidance-surgical-dental-blood-risk.html">http://transmissiblespongiformencephalopathy.blogspot.com/2013/01/tse-guidance-surgical-dental-blood-risk.html</a>
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</div>
<div>
</div>
<div>
Saturday, May 25, 2013</div>
<br />
<div>
</div>
<br />
<div>
Brain homogenates from human tauopathies induce tau inclusions in mouse
brain</div>
<br />
<div>
</div>
<br />
<div>
<a href="http://tauopathies.blogspot.com/2013/05/brain-homogenates-from-human.html">http://tauopathies.blogspot.com/2013/05/brain-homogenates-from-human.html</a>
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</div>
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</div>
<div>
Sunday, June 9, 2013 </div>
<br />
<div>
</div>
<br />
<div>
TSEAC March 14, 2013: Transmissible Spongiform Encephalopathies Advisory
Committee Meeting Webcast </div>
<br />
<div>
</div>
<br />
<div>
<a href="http://tseac.blogspot.com/2013/06/tseac-march-14-2013-transmissible.html">http://tseac.blogspot.com/2013/06/tseac-march-14-2013-transmissible.html</a>
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<div>
Tuesday, May 28, 2013 </div>
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</div>
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Late-in-life surgery associated with Creutzfeldt-Jakob disease: a
methodological outline for evidence-based guidance </div>
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<a href="http://creutzfeldt-jakob-disease.blogspot.com/2013/05/late-in-life-surgery-associated-with.html">http://creutzfeldt-jakob-disease.blogspot.com/2013/05/late-in-life-surgery-associated-with.html</a>
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<a href="http://transmissiblespongiformencephalopathy.blogspot.com/">http://transmissiblespongiformencephalopathy.blogspot.com/</a>
</div>
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<a href="http://bseusa.blogspot.com/">http://bseusa.blogspot.com/</a>
</div>
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<a href="http://nor-98.blogspot.com/">http://nor-98.blogspot.com/</a>
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<a href="http://scrapie-usa.blogspot.com/">http://scrapie-usa.blogspot.com/</a>
</div>
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<a href="http://chronic-wasting-disease.blogspot.com/">http://chronic-wasting-disease.blogspot.com/</a>
</div>
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<a href="http://creutzfeldt-jakob-disease.blogspot.com/">http://creutzfeldt-jakob-disease.blogspot.com/</a>
</div>
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<a href="http://madcowusda.blogspot.com/">http://madcowusda.blogspot.com/</a>
</div>
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<a href="http://betaamyloidcjd.blogspot.com/">http://betaamyloidcjd.blogspot.com/</a>
</div>
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<a href="http://prionopathy.blogspot.com/">http://prionopathy.blogspot.com/</a>
</div>
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<a href="http://proteinopathies.blogspot.com/">http://proteinopathies.blogspot.com/</a>
</div>
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<a href="http://tauopathies.blogspot.com/">http://tauopathies.blogspot.com/</a>
</div>
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TSS</div>
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</div>
Terry S. Singeltary Sr.http://www.blogger.com/profile/06986622967539963260noreply@blogger.com0tag:blogger.com,1999:blog-6491423064023155264.post-71762392603215328372013-05-25T16:39:00.001-05:002013-05-25T16:39:24.051-05:00Brain homogenates from human tauopathies induce tau inclusions in mouse brain<div>
Published online before print May 20, 2013, doi: 10.1073/pnas.1301175110
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PNAS May 20, 2013 </div>
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Brain homogenates from human tauopathies induce tau inclusions in mouse
brain </div>
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Florence Clavagueraa, Hiroyasu Akatsub, Graham Fraserc, R. Anthony
Crowtherc, Stephan Franka, Jürgen Hencha, Alphonse Probsta, David T. Winklera,d,
Julia Reichwalde, Matthias Staufenbiele, Bernardino Ghettif, Michel
Goedertc,1,2, and Markus Tolnaya,1,2 </div>
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aDepartment of Neuropathology, Institute of Pathology, University Hospital,
4031 Basel, Switzerland; bChoju Medical Institute, Fukushimura Hospital,
Toyohashi City 441-8124, Japan; cMedical Research Council Laboratory of
Molecular Biology, Cambridge CB2 0QH, United Kingdom; dDepartment of Neurology,
University Hospital, 4031 Basel, Switzerland; eNovartis Institutes for
Biomedical Research, 4056 Basel, Switzerland; and fIndiana Alzheimer Disease
Center and Department of Pathology and Laboratory Medicine, Indiana University,
Indianapolis, IN 46202 </div>
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Edited by Anders Bjorklund, Lund University, Lund, Sweden, and approved
April 25, 2013 (received for review January 18, 2013) </div>
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Filamentous inclusions made of hyperphosphorylated tau are characteristic
of numerous human neurodegenerative diseases, including Alzheimer’s disease,
tangle-only dementia, Pick disease, argyrophilic grain disease (AGD),
progressive supranuclear palsy, and corticobasal degeneration. In Alzheimer’s
disease and AGD, it has been shown that filamentous tau appears to spread in a
stereotypic manner as the disease progresses. We previously demonstrated that
the injection of brain extracts from human mutant P301S tau-expressing
transgenic mice into the brains of mice transgenic for wild-type human tau (line
ALZ17) resulted in the assembly of wild-type human tau into filaments and the
spreading of tau inclusions from the injection sites to anatomically connected
brain regions. Here we injected brain extracts from humans who had died with
various tauopathies into the hippocampus and cerebral cortex of ALZ17 mice.
Argyrophilic tau inclusions formed in all cases and following the injection of
the corresponding brain extracts, we recapitulated the hallmark lesions of AGD,
PSP and CBD. Similar inclusions also formed after intracerebral injection of
brain homogenates from human tauopathies into nontransgenic mice. Moreover, the
induced formation of tau aggregates could be propagated between mouse brains.
These findings suggest that once tau aggregates have formed in discrete brain
areas, they become self-propagating and spread in a prion-like manner. </div>
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snip... </div>
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The present work indicates that once small numbers of tau inclusions have
formed in the brain, they may become selfpropagating and spread in a prion-like
manner, independently of other pathogenic mechanisms. What is true of aggregated
human tau may also be the case of other aggregation-prone proteins that cause
human neurodegenerative diseases, including α-synuclein, superoxide dismutase 1,
huntingtin, trans-activator regulatory (TAR) DNA-binding protein 43 (TDP-43),
and Aβ (47). The inhibition of cell-to-cell transmission of pathological
aggregates, for instance by passive immunotherapy, may constitute an effective
mechanism-based therapeutic strategy for most human neurodegenerative diseases.
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<a href="http://www.pnas.org/content/early/2013/05/17/1301175110.full.pdf+html">http://www.pnas.org/content/early/2013/05/17/1301175110.full.pdf+html</a>
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Tuesday, May 21, 2013 </div>
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IS ALZHEIMER’S DISEASE A PRION DISEASE? the possible secondary transmission
by blood transfusion are posed</div>
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<a href="http://betaamyloidcjd.blogspot.com/2013/05/is-alzheimers-disease-prion-disease.html">http://betaamyloidcjd.blogspot.com/2013/05/is-alzheimers-disease-prion-disease.html</a>
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Tuesday, May 7, 2013 </div>
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Proteinopathies, a core concept for understanding and ultimately treating
degenerative disorders? </div>
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<a href="http://proteinopathies.blogspot.com/2013/05/proteinopathies-core-concept-for.html">http://proteinopathies.blogspot.com/2013/05/proteinopathies-core-concept-for.html</a>
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Wednesday, May 16, 2012 </div>
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Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion
disease, Iatrogenic, what if ? </div>
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Background </div>
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Alzheimer’s disease and Transmissible Spongiform Encephalopathy disease
have both been around a long time, and was discovered in or around the same time
frame, early 1900’s. Both diseases are incurable and debilitating brain disease,
that are in the end, 100% fatal, with the incubation/clinical period of the
Alzheimer’s disease being longer (most of the time) than the TSE prion disease.
Symptoms are very similar, and pathology is very similar. </div>
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Methods </div>
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Through years of research, as a layperson, of peer review journals,
transmission studies, and observations of loved ones and friends that have died
from both Alzheimer’s and the TSE prion disease i.e. Heidenhain Variant
Creutzfelt Jakob Disease CJD. </div>
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Results </div>
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I propose that Alzheimer’s is a TSE disease of low dose, slow, and long
incubation disease, and that Alzheimer’s is Transmissible, and is a threat to
the public via the many Iatrogenic routes and sources. It was said long ago that
the only thing that disputes this, is Alzheimer’s disease transmissibility, or
the lack of. The likelihood of many victims of Alzheimer’s disease from the many
different Iatrogenic routes and modes of transmission as with the TSE prion
disease. </div>
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Conclusions </div>
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There should be a Global Congressional Science round table event set up
immediately to address these concerns from the many potential routes and sources
of the TSE prion disease, including Alzheimer’s disease, and a emergency global
doctrine put into effect to help combat the spread of Alzheimer’s disease via
the medical, surgical, dental, tissue, and blood arena’s. All human and animal
TSE prion disease, including Alzheimer’s should be made reportable in every
state, and Internationally, WITH NO age restrictions. Until a proven method of
decontamination and autoclaving is proven, and put forth in use universally, in
all hospitals and medical, surgical arena’s, or the TSE prion agent will
continue to spread. IF we wait until science and corporate politicians wait
until politics lets science _prove_ this once and for all, and set forth
regulations there from, we will all be exposed to the TSE Prion agents, if that
has not happened already. </div>
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end...tss </div>
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SEE FULL TEXT AND SOURCE REFERENCES ; </div>
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Wednesday, May 16, 2012 </div>
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Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion
disease, Iatrogenic, what if ? </div>
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Proposal ID: 29403 </div>
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<a href="http://betaamyloidcjd.blogspot.com/2012/05/alzheimers-disease-and-transmissible.html">http://betaamyloidcjd.blogspot.com/2012/05/alzheimers-disease-and-transmissible.html</a>
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Wednesday, September 21, 2011 </div>
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PrioNet Canada researchers in Vancouver confirm prion-like properties in
Amyotrophic Lateral Sclerosis (ALS) </div>
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<a href="http://transmissiblespongiformencephalopathy.blogspot.com/2011/09/prionet-canada-researchers-in-vancouver.html">http://transmissiblespongiformencephalopathy.blogspot.com/2011/09/prionet-canada-researchers-in-vancouver.html</a>
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Sunday, February 10, 2013 </div>
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Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a
Prion-Like Disorder? </div>
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<a href="http://betaamyloidcjd.blogspot.com/2013/02/parkinsons-disease-and-alpha-synuclein.html">http://betaamyloidcjd.blogspot.com/2013/02/parkinsons-disease-and-alpha-synuclein.html</a>
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Ann N Y Acad Sci. 1982;396:131-43. </div>
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Alzheimer's disease and transmissible virus dementia (Creutzfeldt-Jakob
disease). </div>
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Brown P, Salazar AM, Gibbs CJ Jr, Gajdusek DC. </div>
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Abstract </div>
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Ample justification exists on clinical, pathologic, and biologic grounds
for considering a similar pathogenesis for AD and the spongiform virus
encephalopathies. However, the crux of the comparison rests squarely on results
of attempts to transmit AD to experimental animals, and these results have not
as yet validated a common etiology. Investigations of the biologic similarities
between AD and the spongiform virus encephalopathies proceed in several
laboratories, and our own observation of inoculated animals will be continued in
the hope that incubation periods for AD may be even longer than those of CJD.
</div>
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<a href="http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.1982.tb26849.x/abstract">http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.1982.tb26849.x/abstract</a>
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CJD1/9 0185 Ref: 1M51A </div>
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IN STRICT CONFIDENCE </div>
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Dr McGovern From: Dr A Wight Date: 5 January 1993 Copies: Dr Metters Dr
Skinner Dr Pickles Dr Morris Mr Murray </div>
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TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES </div>
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1. CMO will wish to be aware that a meeting was held at DH yesterday, 4
January, to discuss the above findings. It was chaired by Professor Murray
(Chairman of the MRC Co-ordinating Committee on Research in the Spongiform
Encephalopathies in Man), and attended by relevant experts in the fields of
Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the
spongiform encephalopathies, and by representatives of the MRC and AFRC. 2.
Briefly, the meeting agreed that: </div>
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i) Dr Ridley et als findings of experimental induction of p amyloid in
primates were valid, interesting and a significant advance in the understanding
of neurodegenerative disorders; </div>
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ii) there were no immediate implications for the public health, and no
further safeguards were thought to be necessary at present; and </div>
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iii) additional research was desirable, both epidemiological and at the
molecular level. Possible avenues are being followed up by DH and the MRC, but
the details will require further discussion. 93/01.05/4.1 </div>
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<a href="http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf">http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf</a>
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BSE101/1 0136 </div>
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IN CONFIDENCE </div>
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5 NOV 1992 CMO From: Dr J S Metters DCMO 4 November 1992 </div>
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TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES </div>
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1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have
recognized the public sensitivity of these findings and intend to report them in
their proper context. This hopefully will avoid misunderstanding and possible
distortion by the media to portray the results as having more greater
significance than the findings so far justify. </div>
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<div>
2. Using a highly unusual route of transmission (intra-cerebral injection)
the researchers have demonstrated the transmission of a pathological process
from two cases one of severe Alzheimer's disease the other of
Gerstmann-Straussler disease to marmosets. However they have not demonstrated
the transmission of either clinical condition as the "animals were behaving
normally when killed'. As the report emphasizes the unanswered question is
whether the disease condition would have revealed itself if the marmosets had
lived longer. They are planning further research to see if the conditions, as
opposed to the partial pathological process, is transmissible. What are the
implications for public health? </div>
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3. The route of transmission is very specific and in the natural state of
things highly unusual. However it could be argued that the results reveal a
potential risk, in that brain tissue from these two patients has been shown to
transmit a pathological process. Should therefore brain tissue from such cases
be regarded as potentially infective? Pathologists, morticians, neuro surgeons
and those assisting at neuro surgical procedures and others coming into contact
with "raw" human brain tissue could in theory be at risk. However, on a priori
grounds given the highly specific route of transmission in these experiments
that risk must be negligible if the usual precautions for handling brain tissue
are observed. </div>
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92/11.4/1-1 BSE101/1 0137 </div>
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4. The other dimension to consider is the public reaction. To some extent
the GSS case demonstrates little more than the transmission of BSE to a pig by
intra-cerebral injection. If other prion diseases can be transmitted in this way
it is little surprise that some pathological findings observed in GSS were also
transmissible to a marmoset. But the transmission of features of Alzheimer's
pathology is a different matter, given the much greater frequency of this
disease and raises the unanswered question whether some cases are the result of
a transmissible prion. The only tenable public line will be that "more research
is required" before that hypothesis could be evaluated. The possibility on a
transmissible prion remains open. In the meantime MRC needs carefully to
consider the range and sequence of studies needed to follow through from the
preliminary observations in these two cases. Not a particularly comfortable
message, but until we know more about the causation of Alzheimer's disease the
total reassurance is not practical. </div>
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JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832
121/YdeS 92/11.4/1.2 </div>
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<a href="http://collections.europarchive.org/tna/20080102232842/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf">http://collections.europarchive.org/tna/20080102232842/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf</a>
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BSE101/1 0136 </div>
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IN CONFIDENCE </div>
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CMO </div>
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From: Dr J S Metters DCMO </div>
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4 November 1992 </div>
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TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES </div>
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<a href="http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf">http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf</a>
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CJD1/9 0185 </div>
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Ref: 1M51A </div>
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IN STRICT CONFIDENCE </div>
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From: Dr. A Wight Date: 5 January 1993 </div>
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Copies: </div>
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Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray </div>
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TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES </div>
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<a href="http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf">http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf</a>
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Wednesday, January 5, 2011 </div>
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ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011 Prions
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David W. Colby1,* and Stanley B. Prusiner1,2 </div>
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<a href="http://cshperspectives.cshlp.org/content/3/1/a006833.full.pdf+html">http://cshperspectives.cshlp.org/content/3/1/a006833.full.pdf+html</a>
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<a href="http://betaamyloidcjd.blogspot.com/2011/01/enlarging-spectrum-of-prion-like.html">http://betaamyloidcjd.blogspot.com/2011/01/enlarging-spectrum-of-prion-like.html</a>
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Friday, September 3, 2010</div>
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Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids,
Prionpathy, Prionopathy, TSE </div>
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<a href="http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html">http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html</a>
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<a href="http://betaamyloidcjd.blogspot.com/">http://betaamyloidcjd.blogspot.com/</a>
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SCENARIO 3: ‘THE THIN STEMMED GLASS’ </div>
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... a TSE is found that is linked to Alzheimer’s disease. </div>
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<a href="http://madcowtesting.blogspot.com/2012/12/canada-19-cases-of-mad-cow-disease.html">http://madcowtesting.blogspot.com/2012/12/canada-19-cases-of-mad-cow-disease.html</a>
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Thursday, January 17, 2013 </div>
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TSE guidance, surgical, dental, blood risk factors, Part 4 Infection
control of CJD, vCJD and other human prion diseases in healthcare and community
settings (updated January 2013) </div>
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<a href="http://transmissiblespongiformencephalopathy.blogspot.com/2013/01/tse-guidance-surgical-dental-blood-risk.html">http://transmissiblespongiformencephalopathy.blogspot.com/2013/01/tse-guidance-surgical-dental-blood-risk.html</a>
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TSS</div>
Terry S. Singeltary Sr.http://www.blogger.com/profile/06986622967539963260noreply@blogger.com0