Wednesday, July 6, 2016

Effect of Fragmented Pathogenic α-Synuclein Seeds on Prion-like Propagation

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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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 Downloaded from http://www.jbc.org/ by guest on July 6, 2016 Prion-like properties of alpha-synuclein fibrils


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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.


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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.


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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.


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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.


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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.




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

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