Effect of Fragmented Pathogenic α-Synuclein Seeds on Prion-like
Propagation
Airi Tarutani1, Genjiro Suzuki1, Aki Shimozawa1, Takashi Nonaka1, Haruhiko
Akiyama1, Shin-ichi Hisanaga2 and Masato Hasegawa1*
+ Author Affiliations 1 Tokyo Metropolitan Institute of Medical Science,
Japan; 2 Tokyo Metropolitan University, Japan ↵* Corresponding author; email:
hasegawa-ms@igakuken.or.jp
Author contributions: M.H. and A.T. designed the research and wrote the
manuscript. A.T. performed most of the biochemical and immunofluorescence
experiments. A.S. performed immunohistochemistry analysis. H.A, T.N. and G.S.
provided key reagents and conducted the experiments in cellular models. S.H.,
T.N., G.S., A.T. and M.H. analyzed the data.
Abstract
Aggregates of abnormal proteins are widely observed in neuronal and glial
cells of patients with various neurodegenerative diseases, and it has been
proposed that prion-like behavior of these proteins can account for not only the
onset, but also the progression of these diseases. However, it is not yet clear
which abnormal protein structures function most efficiently as seeds for
prion-like propagation. In this study, we aimed to identify the most pathogenic
species of α-synuclein (α-syn), the main component of the Lewy bodies and Lewy
neurites that are observed in α-synucleinopathies. We prepared various forms of
α-syn protein and examined their seeding properties in vitro, in cells and in
mouse experimental models. We also characterized these α-syn species by means of
electron microscopy and thioflavin fluorescence assays, and found that
fragmented beta-sheet-rich fibrous structures of α-syn with a length of 50 nm or
less are the most efficient promoters of accumulation of phosphorylated α-syn,
which is the hallmark of α-synucleinopathies. These results indicate that
fragmented amyloid-like aggregates of short α-syn fibrils are the key pathogenic
seeds that trigger prion-like conversion.
amyloid Parkinson disease prion synuclein Tau protein (Tau) Received April
25, 2016. Accepted July 5, 2016.
DISCUSSION
Many in vitro and in vivo experimental models have demonstrated that the
intracellular abnormal proteins characteristic of major neurodegenerative
diseases, such as α-syn in PD, tau in AD and TDP-43 in ALS/frontotemporal lobar
degeneration (FTLD) have prion-like properties, and that the intracellular
conversion of normal proteins into abnormal forms and cell-to-cell spreading of
the abnormal forms can occur. To understand the relationships between the
phenomena in experimental models and those in brains of patients, we
investigated the prion-like properties (transmissibility) of various α-syn
species in vitro, in cells and in animal models as previously reported (19,20).
Our findings indicate that short α-syn fibrils with lengths of less than 50 nm
are the most effective molecular triggers of formation and spreading of abnormal
α-syn, by acting as seeds for prion-like conversion in cultured cells and mouse
brains.
In our in vitro experiment, conversion of normal soluble α-syn into
amyloid-like fibrils was accelerated by addition of small amounts of preformed
α-syn fibrils, and the acceleration was increased in proportion to the
sonication time of fibrils (Fig. 5D), suggesting that fragmentation of the
fibrils is important for the prion-like conversion. Indeed, the similarity of
kinetics of α-syn fibril formation seeded with unsonicated fibrils and 1/40 or
1/60 diluted sonicated fibrils implies that the seeding activity was dependent
on the number of fibrils ends and that the number of fibrils was increased 40 to
60 times after sonication for 180 seconds (Fig. 5E). This seems consistent with
the observed lengths of fibrils (Fig. 5B). In cultured cells, introduction of
fragmented α-syn fibrils also promoted seed-dependent aggregation (Fig. 6A).
This finding is consistent with a previous report showing that short fibrils
induce seeded aggregation of endogenous α-syn in cultured cells without
overexpression (35). We also found that increased cytotoxicity was correlated
with increased accumulation of intracellular phosphorylated α-syn aggregates
(Fig. 6C), but the observed cytotoxicities were comparatively low. This low
propensity for
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7
cytotoxicity may be consistent with the extremely long silent period from
the accumulation of α-syn aggregates until neuronal loss in patient’s brains. In
mice, fragmented α-syn fibrils in which more than 80 % of fragments were less
than 50 nm in size were the most efficient for prion-like propagation (Fig. 7A).
Although exogenously injected α-syn fibrils were degraded within a week (19),
fragmented fibrils may continue to act on endogenous mouse α-syn until they are
digested, generating widespread pathology. Therefore, control of propagation may
require a focus on newly generated seeds.
Lewy bodies and Lewy neurites observed in patients are composed of
filamentous α-syn 200-600 nm in length and 5-10 nm in width (14). Similarly,
immuno-EM of α-syn fibril-injected wild-type mouse brain in this study revealed
numerous comparatively long fibrous structures with approximately ~10 nm width
around nuclei (Fig. 9A). The accumulations of fibrous structures were also
confirmed by immuno-EM of sarkosyl-insoluble fraction of mouse brains with
antibodies specific for mouse α-syn and phosphorylated α-syn (Fig. 9B). These
results indicated that recombinant α-syn fibrils acted as a pathogenic factor to
convert endogenous mouse α-syn into amyloid-like fibrils. Furthermore,
sonication of sarkosyl-insoluble fractions containing these fibrils resulted in
enhancement of the seeding activity in cultured cells (Fig. 9D), raising the
possibility that the breaking of once-elongated fibrils into short fragments in
vivo enhances the prion-like activities of seeds, promoting cell-to-cell
spreading. This is consistent with a report that fragmented amyloid-like fibrils
have distinct properties from long fibrils (33), indicating that fragmentation
of fibrous structures may be a critical first step in transmission.
Many studies on prion-like proteins in experimental models have suggested
that sonication of amyloid or amyloid-like fibrils significantly enhances
seeding activity. Fragmented amyloid fibrils induced cytotoxicity in vitro (33)
and small soluble Aβ seeds found in brain extracts isolated from APP transgenic
mice caused intracerebral propagation in vivo (36). On the other hand, Wu et al.
reported that small tau aggregates were internalized in neuronal cells (32), and
Jackson and Kerridge et al. demonstrated that short fibrous tau assemblies with
an average length of 179 nm isolated from P301S tau mice induced seed-dependent
propagation in vivo (37). These findings are broadly consistent with our finding
that fibrous α-syn seeds less than 50 nm in length (approximately 40 % of them
were only 25 nm) have the highest seeding activity in the prion-like
propagation. It is plausible that smaller structures would be more easily
incorporated into cells by endocytosis. There is evidence that α-syn fibrous
structures interact with cellular membranes, can move between cells, and are
secreted from axons (38,39). Additionally, Pieri et al. reported that α-syn
fibrils are more cytotoxic than oligomeric species (40). The presence of short
fibrous structures in the supernatants after ultracentrifugation (41) or
high-speed centrifugation (Fig. 4B) supports the possibility that oligomers
(considered as intermediates of fibrils) may include quite short fibrils. In
prion proteins, nonfibrillar small particles showed the most infectivity and
sonication enhance their transmissibility (42). Taking these results together,
it seems that there are common features in the cell-to-cell spreading and
transmission of pathogenic species of various prions and prion-like
proteins.
In general, sonicated recombinant α-syn fibrils are used to induce
cell-to-cell spreading in cellular and animal experimental models (23,43), and
it can be difficult to establish the relevance of such studies to the prion-like
propagation seen in patients with α-synucleinopathies. However, advantages of
that approach are that well-characterized short fibrils can be prepared, and
inoculation samples are not contaminated with other factors that might influence
propagation. However, there are clearly issues over interpretation, because our
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on July 6, 2016 Prion-like properties of alpha-synuclein fibrils
8
data indicate that differences of preparation procedures, including degree
of sonication of preformed α-syn fibrils, can greatly influence the results. It
is also noteworthy that familial PD α-syn mutant A30P fibrils are more fragile
than WT α-syn fibrils (41).
In this work, we investigated the seeding activity of various α-syn species
in various experimental models of prion-like propagation and found that
fragmented β-sheet-rich fibrous α-syn species (50 nm or less in length) were the
most effective in inducing seed-dependent aggregation of α-syn in all the
experimental models. Further study is needed to elucidate the precise mechanisms
underlying the prion-like propagation.
*** PRION2015 Alzheimer’s disease ***
*** P.34: Preliminary study of Alzheimer’s disease transmission to bank
vole
Guido Di Donato1, Geraldina Riccardi1, Claudia D’Agostino1, Flavio
Torriani1, Maurizio Pocchiari2, Romolo Nonno1, Umberto Agrimi1, and Michele
Angelo Di Bari1
1Department of Food Safety and Veterinary Public Health Istituto Superiore
di Sanit a, Rome, Italy; 2Department of Cellular Biology and Neuroscience;
Istituto Superiore di Sanit a, Rome, Italy
Extensive experimental findings indicate that prion-like mechanisms underly
the pathogenesis of Alzheimer disease (AD). Transgenic mice have been pivotal
for investigating prionlike mechanisms in AD, still these models have not been
able so far to recapitulate the complex clinical-pathological features of AD.
Here we aimed at investigating the potential of bank vole, a wild-type rodent
highly susceptible to prions, in reproducing AD pathology upon experimental
inoculation.
Voles were intracerebrally inoculated with brain homogenate from a familial
AD patient. Animals were examined for the appearance of neurological signs until
the end of experiment (800 d post-inoculation, d.p.i.). Brains were studied by
immunohistochemistry for pTau Prion 2015 Poster Abstracts S29 (with AT180 and
PHF-1 antibodies) and b-amyloid (4G8).
Voles didn’t show an overt clinical signs, still most of them (11/16) were
found pTau positive when culled for intercurrent disease or at the end of
experiment. Interestingly, voles culled as early as 125 d.p.i. already showed
pTau aggregates. Deposition of pTau was similar in all voles and was
characterized by neuropil threads and coiled bodies in the alveus, and by rare
neurofibrillary tangles in gray matter. Conversely, b-amyloid deposition was
rather rare (2/16). Nonetheless, a single vole showed the contemporaneous
presence of pTau in the alveus and a few Ab plaque-like deposits in the
subiculum. Uninfected age-matched voles were negative for pTau and Ab.
*** These findings corroborate and extend previous evidences on the
transmissibility of pTau and Ab aggregation. Furthermore, the observation of a
vole with contemporaneous propagation of pTau and Ab is intriguing and deserves
further studies.
=================
P.155: Quantitative real-time analysis of disease specific tau amyloid
seeding activity
Davin Henderson and Edward Hoover Prion Research Center; College of
Veterinary Medicine and Biomedical Sciences; Colorado State University; Fort
Collins, CO USA
A leading hypothesis for the cause of neurodegenerative diseases is the
templated misfolding of cellular proteins to an amyloid state. Spongiform
encephalopathies were the first diseases discovered to be caused by a misfolded
amyloid-rich protein. It is now recognized that the major human
neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s
disease (PD), and chronic traumatic encephalopathy (CTE), also are associated
with amyloid formation. Moreover, AD and PD amyloids have been shown competent
to transmit disease in experimental animal models, suggesting shared mechanisms
with traditional prion diseases. Sensitive detection of prion disease has been
advanced by in vitro amplification of low levels of disease specific amyloid
seeds, e.g. serial protein misfolding amplification (sPMCA), amyloid seeding
(ASA) and real-time quaking induced conversion (RT-QuIC), thereby replicating
the disease process in vitro. In addition, measurement of the amyloid formation
rate can estimate the level of disease-associated seed by using methods
analogous to quantitative polymerase chain reaction (qPCR). In the present work,
we apply these principles to show that seeding activity of in vitro generated
amyloid tau and AD brain amyloid tau can be readily detected and
quantitated.
=============
P.83: Gerstmann-Str€aussler-Scheinker disease with F198S mutation:
Selective propagation of PrPSc and pTau upon inoculation in bank vole
Michele Angelo Di Bari1, Romolo Nonno1, Laura Pirisinu1, Claudia
D’Agostino1, Geraldina Riccardi1, Guido Di Donato1, Paolo Frassanito1,
Bernardino Ghetti2, Pierluigi Gambetti3, and Umberto Agrimi1
1Department of Veterinary Public Health and Food Safety; Istituto Superiore
di Sanit a; Rome, Italy;
2Indiana University-Purdue University Indianapolis; Department of Pathology
and Laboratory Medicine; Indianapolis, IN USA; 3Case Western Reserve University;
Cleveland, OH USA
Gerstmann-Str€aussler-Scheinker disease with F198S mutation (GSS-F198S) is
characterized by the presence of PrP amyloid plaques as well as neurofibrillary
tangles with abnormally-phosphorylated tau protein (pTau) in the brain. The
relationship between tau protein and PrP in the pathogenesis of GSS-F198S is
unknown. In a previous study, we inoculated intracerebrally 2 GSS-F198S cases in
2 lines of voles carrying either methionine (Bv109M) or isoleucine (Bv109I) at
codon 109 of PrP. GSS-F198S transmitted rather efficiently to Bv109I, but not to
Bv109M.
Here we investigated the presence of pTau, as assessed by
immunohistochemistry with anti-pTau antibodies AT180 and PHF-1, in the same
voles previously inoculated with GSSF198S. Among these voles, most Bv109I showed
clinical signs after short survival times (»150 d.p.i.) and were positive for
PrPSc. The remaining Bv109I and all Bv109M survived for longer times without
showing prion-related pathology or detectable PrPSc. All Bv109I which were
previously found PrPSc-positive,
S54 Prion 2015 Poster Abstracts
were immunonegative for pTau deposition. In contrast, pTau deposition was
detected in 16/20 voles culled without clinical signs after long survival times
(225–804 d.p.i.). pTau deposition was characterized by neuropil threads and
coiled bodies in the alveus, and was similar in all voles analyzed.
These findings highlight that pTau from GSS-F198S can propagate in voles.
Importantly, pTau propagation was independent from PrPSc, as pTau was only found
in PrPSc-negative voles surviving longer than 225 d.p.i. Thus, selective
transmission of PrPSc and pTau proteinopathies from GSS-F198S can be
accomplished by experimental transmission in voles.
=========
I3 Aβ Strains and Alzheimer’s Disease
Lary Walker Emory University, Atlanta, GA, USA
An essential early event in the development of Alzheimer’s disease is the
misfolding and aggregation of Aβ. Enigmatically, despite the extensive
deposition of human-sequence Aβ in the aging brain, nonhuman primates do not
develop the full pathologic or cognitive phenotype of Alzheimer’s disease, which
appears to be unique to humans. In addition, some humans with marked Aβ
accumulation in the brain retain their cognitive abilities, raising the question
of whether the pathogenicity of Aβ is linked to the molecular features of the
misfolded protein. I will present evidence for strain-like molecular differences
in aggregated Aβ between humans and nonhuman primates, and among end-stage
Alzheimer patients. I will also discuss a case of Alzheimer’s disease with
atypical Aβ deposition to illustrate heterogeneity in the molecular architecture
of Aβ assemblies, and how this variability might influence the nature of the
disease. As in the case of prion diseases, strain-like variations in the
molecular architecture of Aβ could help to explain the phenotypic variability in
Alzheimer’s disease, as well as the distinctively human susceptibility to the
disorder.
This research was conducted in collaboration with Harry LeVine, Rebecca
Rosen, Amarallys Cintron, David Lynn, Yury Chernoff, Anil Mehta and Mathias
Jucker and colleagues. Supported by AG040589, RR165/OD11132, AG005119, NS077049,
the CART Foundation and MetLife.
==========
I5 Pathogenic properties of synthetically generated prions
Jiyan Ma Van Andel Research Institute, Grand Rapids, Michigan, USA
Synthetically generating prions with bacterially expressed recombinant
prion protein (recPrP) strongly supports the prion hypothesis. Yet, it remains
unclear whether the pathogenic properties of synthetically generated prions
(rec-Prion) fully recapitulate those of naturally occurring prions. A series of
analyses including intracerebral and intraperitoneal transmissions of rec-Prion
in wild-type mice were performed to determine the characteristics of rec-Prion
induced diseases. Results from these analyses demonstrated that the rec-Prion
exhibits the same pathogenic properties with naturally occurring prions,
including a titratable infectivity that can be determined by endpoint titration
assays, capability of transmitting prion disease via routes other than the
direct intra-cerebral inoculation, causing ultra-structural lesions that are
specific to prion disease, and sharing a similar manner of visceral
dissemination and neuroinvasion with naturally occurring scrapie and chronic
wasting disease. These findings confirmed that the disease caused by rec-Prion
in wild-type mice is bona fide prion disease or transmissible spongiform
encephalopathiges, and the rec-Prion contains similar pathogenic properties as
naturally occurring prions.
I6 Transmissible protein toxins in neurodegenerative disease
Jacob Ayers, David Borchelt University of Florida, Gainesville, FL,
USA
Amyotrophic lateral sclerosis (ALS) is an obvious example of
neurodegenerative disease that seems to spread along anatomical pathways. The
spread of symptoms from the site of onset (e.g. limb) to the respiratory
musculature drives the rate of disease progression. In cognitive disorders, such
as Alzheimer’s disease, one can find similarly find evidence of spreading
dysfunction and pathology. One mechanism to account for this spread of disease
from one neural structure to another is by evoking prion-like propagation of a
toxic misfolded protein from cell to cell. Recent studies in animals that model
aspects of Alzheimer’s Disease, Parkinson’s Disease, and Tauopathy, have
bolstered the arguments in favor of prion-like, although in most of these models
the mice do not develop overt “clinical” symptoms. Recently, Jacob Ayers
demonstrated that the symptoms of ALS can be transmitted from a strain of mice
that expresses mutant SOD1-G93A at high levels to a second transgenic strain
that expresses mutant SOD1 at low, nontoxic, levels. This model showed many
prion-like features including evidence of host-adaptation (earlier and more
penetrant disease upon second passage). Interestingly, homogenates from
paralyzed mice expressing the G37R variant of SOD1 transmitted poorly, a finding
suggestive that different SOD1 variants may exhibit strain-like properties.
These “ i n d u c i b l e ” m o d e l s o f h u m a n neurodegenerative disease
enable the generation of models that do not require extraordinary levels of
transgene expression and provide a more precise means of initiating the disease
process, advances that may translate into more predictive pre-clinical
models.
=======
P188 Transmission of amyloid pathology by peripheral administration of
misfolded Aβ
Javiera Bravo-Alegria1 ,2, Rodrigo Morales2, Claudia Duran-Aniotz3, Claudio
Soto2 1University of Los Andes, Santiago, Chile, 2Mitchell Center for
Alzheimer’s Disease and Related Brain Disorders, Department of Neurology,
University of Texas Medical School, Houston, Texas, USA, 3University of Chile,
Santiago, Chile
Misfolding and aggregation of Amyloid-β (Aβ) is one of the primary events
involved in the pathogenesis of Alzheimer's disease (AD). Recently, it has been
proposed that Aβ aggregates can transmit and spread the pathology following a
prion-like mechanism. Prions can be exogenously transmitted by many different
routes of administration. In the case of Aβ, previous studies showed that
intraperitoneal (i.p.) injection of seeds can accelerate cerebral amyloidosis in
mouse models. However, other potential routes have not yet been studied. The
goal of this work was to assess whether Aβ amyloidosis can be seeded in the
brain of a transgenic mouse model of AD by peripheral administration of
misfolded particles.
Young tg2576 animals (50 days old) were inoculated with a pool of brain
extract coming from old Tg2576 animals (10%w/v) by different routes: i.p.
(100μL), eye drops (5μL each eye, 3 times), intramuscular (i.m., 50μL), and per
os (p.o., 1000μL). Animals were sacrificed at 300 days old, and brain samples
were analyzed for amyloid pathology by IHC and ELISA.
The i.p., i.m., and eye drops administration of Aβ seeds significantly
accelerated pathological features in tg2576. Regardless of the higher volume
administered, p.o. treated animals did not show any pathological changes when
compared to untreated controls. Differences in the proportion of diffuse, core
and vascular deposition was observed within experimental groups. Our data show
that peripheral administration of Aβ seeds could accelerate pathological changes
in the brain and suggest that an orchestrated cross-talk between the brain and
peripheral tissues occurs in AD.
==========
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.
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.
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
*** Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes
contaminated during neurosurgery ***
Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC.
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.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8006664&dopt=Abstract
Alzheimer-type brain pathology may be transmitted by grafts of dura
mater
26/01/2016
Wednesday, June 29, 2016
NIH awards $11 million to UTHealth researchers to study deadly CWD prion
diseases Claudio Soto, Ph.D.
Public Release: 29-Jun-2016
Sunday, January 17, 2016
Of Grave Concern Heidenhain Variant Creutzfeldt Jakob Disease
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.
Friday, January 29, 2016
Synucleinopathies: Past, Present and Future, iatrogenic, what if?
Terry S. Singeltary Sr. Bacliff, Texas USA 77518 flounder9@verizon.net
