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

 

 

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