Tuesday, December 6, 2016

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

  1. Stanley B. Prusinera,b,k,2
Author Affiliations
  1. aInstitute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA 94143;
  2. bDepartment of Neurology, University of California, San Francisco, CA 94143;
  3. cDaiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan;
  4. dDepartment of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143;
  5. eDepartment of Pathology, University of California, San Francisco, CA 94143;
  6. fChronic Traumatic Encephalopathy Program, Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA 02118;
  7. gDepartment of Neurology, Boston University School of Medicine, Boston, MA 02118;
  8. hDepartment of Pathology, Boston University School of Medicine, Boston, MA 02118;
  9. iVeterans Affairs Boston Healthcare System, US Department of Veterans Affairs, Jamaica Plain, MA 02130;
  10. jUS Department of Veterans Affairs Medical Center, Bedford, MA 01730;
  11. kDepartment of Biochemistry and Biophysics, University of California, San Francisco, CA 94143
  1. Contributed by Stanley B. Prusiner, October 6, 2016 (sent for review August 5, 2016; reviewed by Robert H. Brown Jr. and David Westaway)
    1. Abstract
    2. Full Text
    3. Authors & Info
    4. Figures
    5. SI
    6. Metrics
    7. Related Content
    8. PDF
    9. PDF + SI

    Significance

    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.

    Abstract

    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.

    Footnotes

    • 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.
    • Reviewers: R.H.B., University of Massachusetts Medical School; and D.W., University of Alberta.
    • 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.
    • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1616344113/-/DCSupplemental.

    http://www.pnas.org/content/early/2016/11/22/1616344113.abstract


    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. 
     
    Applications must be submitted through the Agriculture Funding Consortium website.
     
    ALBERTA ALZHEIMER RESEARCH PROGRAM
     
    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.

    Application Deadline: January 16, 2017
     
     
    EXPLORATIONS

    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.

    Application Deadline: no current competition

    SPECIFIED RISK MATERIALS PROGRAM

    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. 

    Application Deadline: no current competition
     
     RESEARCH TEAM PROGRAM
     
    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.

    Application Deadline: no current competition

     IDeal PROGRAM
     
     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:
    • Protein folding and misfolding in prion diseases;
    • The pathobiology of TSEs;
    • Surveillance and control of prion diseases;
    • Diagnostic technologies;
    • Solutions to enhance market access;
    • Innovative disposal and/or uses of specified risk material;
    • TSEs and society;
    • Protein folding and misfolding in prion-like human neurodegenerative diseases; and
    • Prion-like mechanisms in human neurodegenerative diseases.
       
    Funding may be up to $500,000. Projects may range from one to three years in duration.

    Application Deadline: continuous intake

    GUEST SPEAKER SUPPORT PROGRAM
     
    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.

    Application Deadline: continuous intake
     
    EXPANDING HORIZONS PROGRAM
     
    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.




    Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease

    *** Singeltary comment PLoS ***

    Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic,
    what if ?

    Posted by flounder on 05 Nov 2014 at 21:27 GMT

    http://www.plosone.org/annotation/listThread.action?root=82860

    Sunday, November 22, 2015

    *** Effect of heating on the stability of amyloid A (AA) fibrils and the intra- and cross-species transmission of AA amyloidosis Abstract

    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.

    Purchase options Price * Issue Purchase USD 511.00 Article Purchase USD 54.00

    http://www.tandfonline.com/doi/abs/10.3109/13506129.2015.1095735?journalCode=iamy20

    http://betaamyloidcjd.blogspot.com/2015/11/effect-of-heating-on-stability-of.html
     
    SWISS MEDICAL WEEKLY

    Alzheimer-type brain pathology may be transmitted by grafts of dura mater 26/01/2016 Singeltary comment ;

    http://blog.smw.ch/alzheimer-type-brain-pathology-may-be-transmitted-by-grafts-of-dura-mater/#comment-89016

     re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy

    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)

    snip...see full Singeltary Nature comment here;

    http://www.nature.com/nature/journal/v525/n7568/full/nature15369.html#/comments
     

    Sunday, December 04, 2016

    Heidenhain variant of Creutzfeldt–Jakob disease in a patient who had bovine bioprosthetic valve implantation

    Year : 2016 | Volume : 64 | Issue : 10 | Page : 767-769


    Thursday, December 1, 2016

    PRION2017 DECIPHERING NEURODEGENERATIVE DISORDERS 23 – 26 May 2017 Edinburgh

    http://prionprp.blogspot.com/2016/12/prion2017-deciphering-neurodegenerative.html

    Saturday, December 03, 2016

    TEXAS CHRONIC WASTING DISEASE CWD TSE PRION UPDATE 35 CASES TO DATE



    Thursday, December 1, 2016
     

    The European Union summary report on data of the surveillance of ruminants for the presence of transmissible spongiform encephalopathies (TSEs) in 2015

     
     
     
    Tuesday, November 29, 2016
     
    Transmissibility of Gerstmann–Sträussler–Scheinker syndrome in rodent models: new insights into the molecular underpinnings of prion infectivity
     
     

    Saturday, July 23, 2016

    BOVINE SPONGIFORM ENCEPHALOPATHY BSE TSE PRION SURVEILLANCE, TESTING, AND SRM REMOVAL UNITED STATE OF AMERICA UPDATE JULY 2016

    http://bovineprp.blogspot.com/2016/07/bovine-spongiform-encephalopathy-bse.html


    Tuesday, July 26, 2016

    Atypical Bovine Spongiform Encephalopathy BSE TSE Prion UPDATE JULY 2016

    http://bse-atypical.blogspot.com/2016/07/atypical-bovine-spongiform.html
     

    *** Calling Canadian beef unsafe is like calling your twin sister ugly," Dopp said.

    Thursday, August 25, 2016

    *** 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 ***

    http://specifiedriskmaterial.blogspot.com/2016/08/fsis-green-bay-dressed-beef-recalls.html


    Tuesday, August 9, 2016

    *** Concurrence with OIE Risk Designations for Bovine Spongiform Encephalopathy [Docket No. APHIS-2015-0055]

    http://bovineprp.blogspot.com/2016/08/concurrence-with-oie-risk-designations.html



     why do we not want to do TSE transmission studies on chimpanzees $

    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.

     snip...

     R. BRADLEY

    http://collections.europarchive.org/tna/20080102222950/http://www.bseinquiry.gov.uk/files/yb/1990/09/23001001.pdf


    http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=313160


    SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016

    Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl 1933-690X online



     *** 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.

     *** 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.

     *** 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.

     http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=313160


     O.05: Transmission of prions to primates after extended silent incubation periods: Implications for BSE and scrapie risk assessment in human populations

     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

     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.

     *** We recently observed the direct transmission of a natural classical scrapie isolate to macaque after a 10-year silent incubation period,

     ***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),

     ***is the third potentially zoonotic PD (with BSE and L-type BSE),

     ***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.

     ===============

    ***thus questioning the origin of human sporadic cases***

     ***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.

    https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf
     

    Diagnosis and Reporting of Creutzfeldt-Jakob Disease

    Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA

    Diagnosis and Reporting of Creutzfeldt-Jakob Disease

    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.

    Terry S. Singeltary, Sr Bacliff, Tex

    1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.

    http://jama.jamanetwork.com/article.aspx?articleid=1031186

    26 March 2003

    Terry S. Singeltary, retired (medically) CJD WATCH

    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?

    http://www.neurology.org/content/60/2/176/reply#neurology_el_535

    Sent: Monday, January 08,2001 3:03 PM

    TO: freas@CBS5055530.CBER.FDA.GOV

     FDA CJD BSE TSE Prion Scientific Advisors and Consultants Staff January 2001 Meeting Singeltary Submission

    2001 FDA CJD TSE Prion Singeltary Submission

    http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf

    2 January 2000

    British Medical Journal

    U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well

    http://www.bmj.com/rapid-response/2011/10/28/us-scientist-should-be-concerned-cjd-epidemic-us-well

    15 November 1999

    British Medical Journal

    vCJD in the USA * BSE in U.S.

    http://www.bmj.com/rapid-response/2011/10/28/re-vcjd-usa-bse-us ;;;
     

    Monday, December 5, 2016

    Prion Institute protein folding and misfolding; pathobiology of TSEs; surveillance, control; and TSEs

    http://prionprp.blogspot.com/2016/12/prion-institute-protein-folding-and.html


    Sunday, December 04, 2016

    Heidenhain variant of Creutzfeldt–Jakob disease in a patient who had bovine bioprosthetic valve implantation


    Tuesday, November 29, 2016
     
    Transmissibility of Gerstmann–Sträussler–Scheinker syndrome in rodent models: new insights into the molecular underpinnings of prion infectivity
     


     
    Terry S. Singeltary Sr.
    Bacliff, Texas USA 77518


    Posted by at No comments:

    Thursday, November 27, 2014

    Animal models of tauopathies and their implications for research/translation into the clinic

    Invited Review

     

    Animal models of tauopathies and their implications for research/translation into the clinic

     

    Simon Dujardin, Morvane Colin* and Luc Buée DOI: 10.1111/nan.12200

     

    Author Information

     

    Inserm, UMR1172 Jean-Pierre Aubert research centre, Lille, France ; Université de Lille, Faculté de Médecine, Lille, France; CHRU, Memory Clinic, Lille, France

     

    * 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

     

    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

     

    Publication History Accepted manuscript online: 26 NOV 2014 10:37PM EST Manuscript Accepted: 23 NOV 2014

     

    Keywords:

     

    Alzheimer's disease; prion; propagation; tau protein; phosphorylation; aggregation; neurodegeneration; therapeutic approaches

     

    Abstract

     

    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.

     

    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.

     

    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.

     


     

    Monday, November 17, 2014

     

    Prion-like transmission and spreading of tau pathology

     


     

    Wednesday, June 19, 2013

     

    Spreading of tau pathology in Alzheimer's disease by cell-to-cell transmission

     


     

    Saturday, May 25, 2013

     

    Brain homogenates from human tauopathies induce tau inclusions in mouse brain

     


     


     

    Sunday, November 23, 2014

     

    Transmission Characteristics of Variably Protease-Sensitive Prionopathy

     

    * We concluded that VPSPr is transmissible; thus, it is an authentic prion disease.

     


     


     


     


     

    Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease

     

    Received July 24, 2014; Accepted September 16, 2014; Published November 3, 2014

     


     

    Singeltary comment ;

     


     

    Monday, November 3, 2014

     

    USA CJD TSE PRION UNIT, TEXAS, SURVEILLANCE UPDATE NOVEMBER 2014

     

    National Prion Disease Pathology Surveillance Center Cases Examined1 (October 7, 2014)

     

    ***6 Includes 11 cases in which the diagnosis is pending, and 19 inconclusive cases;

     

    ***7 Includes 12 (11 from 2014) cases with type determination pending in which the diagnosis of vCJD has been excluded.

     

    ***The sporadic cases include 2660 cases of sporadic Creutzfeldt-Jakob disease (sCJD),

     

    ***50 cases of Variably Protease-Sensitive Prionopathy (VPSPr)

     

    ***and 21 cases of sporadic Fatal Insomnia (sFI).

     


     

     Sunday, November 23, 2014

     

    Confirmed Variant Creutzfeldt-Jakob Disease (variant CJD) Case in Texas in June 2014 confirmed as USA case NOT European

     

     
     
     
    TSS
    Posted by at No comments:

    Monday, November 17, 2014

    Prion-like transmission and spreading of tau pathology

    Invited Review

     
    Prion-like transmission and spreading of tau pathology Florence Clavaguera1, Jürgen Hench1, Michel Goedert2 and Markus Tolnay1,* DOI: 10.1111/nan.12197

     
    This article is protected by copyright. All rights reserved.

     
    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

     
    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

     
    Publication History Accepted manuscript online: 17 NOV 2014 01:23AM EST Manuscript Accepted: 13 NOV 2014

     
    Abstract

     
    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.

     
    http://onlinelibrary.wiley.com/doi/10.1111/nan.12197/abstract?campaign=wolacceptedarticle

     

    Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease

     

    Received July 24, 2014; Accepted September 16, 2014; Published November 3, 2014

     


     

    Singeltary comment ;

     


     

    Wednesday, June 19, 2013

     

    Spreading of tau pathology in Alzheimer's disease by cell-to-cell transmission

     


     

    Saturday, May 25, 2013

     

    Brain homogenates from human tauopathies induce tau inclusions in mouse brain

     


     


     


     


     

    Tuesday, November 04, 2014

     

    Towards an Age-Dependent Transmission Model of Acquired and Sporadic Creutzfeldt-Jakob Disease

     


     


     

    Friday, January 10, 2014

     

    vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???

     


     


     

    Monday, November 3, 2014

     

    USA CJD TSE PRION UNIT, TEXAS, SURVEILLANCE UPDATE NOVEMBER 2014

     

    National Prion Disease Pathology Surveillance Center Cases Examined1 (October 7, 2014)

     

    ***6 Includes 11 cases in which the diagnosis is pending, and 19 inconclusive cases;

     

    ***7 Includes 12 (11 from 2014) cases with type determination pending in which the diagnosis of vCJD has been excluded.

     

    ***The sporadic cases include 2660 cases of sporadic Creutzfeldt-Jakob disease (sCJD),

     

    ***50 cases of Variably Protease-Sensitive Prionopathy (VPSPr)

     

    ***and 21 cases of sporadic Fatal Insomnia (sFI).

     


     


     

    TSS
    Posted by at No comments:

    Wednesday, June 19, 2013

    Spreading of tau pathology in Alzheimer's disease by cell-to-cell transmission

    Spreading of tau pathology in Alzheimer's disease by cell-to-cell transmission

     

     

     

     Nguyen-Vi Mohamed, Thibaut Herrou, Vanessa Plouffe, Nicolas Piperno, Nicole Leclerc*

     
     
     

    Article first published online: 16 JUN 2013

     
     
     

    DOI: 10.1111/ejn.12229



     

    © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd

     

     



     

    Keywords:



     

    Alzheimer's disease; endocytosis and secretion; propagation; tau

     



    Abstract
     
     

     

    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.

     

     
     

     

     

     

    Published online before print May 20, 2013, doi: 10.1073/pnas.1301175110

     

    PNAS May 20, 2013

     

     
    Brain homogenates from human tauopathies induce tau inclusions in mouse brain

     

     
    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

     

     
    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

     

     
    Edited by Anders Bjorklund, Lund University, Lund, Sweden, and approved April 25, 2013 (received for review January 18, 2013)

     

     
     
    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.

     

     
     
    snip...

     

     
     
    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.

     

     

     

     
     

     

     

     

     
     
    Tuesday, May 21, 2013

     

    IS ALZHEIMER’S DISEASE A PRION DISEASE? the possible secondary transmission by blood transfusion are posed

     


     

     

     

     
     
    Tuesday, May 7, 2013

     

    Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders?

     


     

     

     

     
     
    Wednesday, May 16, 2012

     

     

     

    Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

     

     Background

     

     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.

     

     Methods

     

     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.

     

     Results

     

     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.

     

     Conclusions

     

     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.

     

     end...tss

     

     
    SEE FULL TEXT AND SOURCE REFERENCES ;

     

     
     
    Wednesday, May 16, 2012

     

    Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

     

    Proposal ID: 29403

     


     

     

     

     
     
    Wednesday, September 21, 2011

     

    PrioNet Canada researchers in Vancouver confirm prion-like properties in Amyotrophic Lateral Sclerosis (ALS)

     


     

     

     

     
     
    Sunday, February 10, 2013

     

    Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a Prion-Like Disorder?

     


     

     

     

     
     
    Ann N Y Acad Sci. 1982;396:131-43.

     

     
    Alzheimer's disease and transmissible virus dementia (Creutzfeldt-Jakob disease).

     

     
    Brown P, Salazar AM, Gibbs CJ Jr, Gajdusek DC.

     

     
    Abstract

     

     
    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.

     

     

     

     

     

     
     
    CJD1/9 0185 Ref: 1M51A

     

    IN STRICT CONFIDENCE

     

    Dr McGovern From: Dr A Wight Date: 5 January 1993 Copies: Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray

     

    TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

     

    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:

     

    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;

     

    ii) there were no immediate implications for the public health, and no further safeguards were thought to be necessary at present; and

     

    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

     


     

     

     

     
     
    BSE101/1 0136

     

    IN CONFIDENCE

     

    5 NOV 1992 CMO From: Dr J S Metters DCMO 4 November 1992

     

    TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

     

    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.

     

    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?

     

    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.

     

    92/11.4/1-1 BSE101/1 0137

     

    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.

     

    JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832 121/YdeS 92/11.4/1.2

     


     

     

     

     
     
    BSE101/1 0136

     

    IN CONFIDENCE

     

    CMO

     

    From: Dr J S Metters DCMO

     

    4 November 1992

     

    TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

     


     

     

     

     
     
    CJD1/9 0185

     

    Ref: 1M51A

     

    IN STRICT CONFIDENCE

     

    From: Dr. A Wight Date: 5 January 1993

     

    Copies:

     

    Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray

     

    TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES

     


     

     

     

     
     
    Wednesday, January 5, 2011

     

    ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011 Prions

     

    David W. Colby1,* and Stanley B. Prusiner1,2

     


     


     

     

     

     
     
    Friday, September 3, 2010

     

    Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE

     


     


     

     

     

     
     
    SCENARIO 3: ‘THE THIN STEMMED GLASS’

     

    ... a TSE is found that is linked to Alzheimer’s disease.

     


     

     

     

     
     
    Thursday, January 17, 2013

     

    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)

     


     

     

     

     
     
    Saturday, May 25, 2013

     

    Brain homogenates from human tauopathies induce tau inclusions in mouse brain

     


     

     

     

     
     
    Sunday, June 9, 2013

     

    TSEAC March 14, 2013: Transmissible Spongiform Encephalopathies Advisory Committee Meeting Webcast

     


     

     

     

     

     

     
     
    Tuesday, May 28, 2013

     

    Late-in-life surgery associated with Creutzfeldt-Jakob disease: a methodological outline for evidence-based guidance

     


     

     

     

     

     

     
     

     

     
     

     

     
     

     

     
     

     

     
     

     

     
     

     

     
     

     

     
     

     

     
     

     

     
     

     

     

     

     
     
    TSS

     

     
    Posted by at No comments:
    Subscribe to: Posts (Atom)