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
