Tuesday, December 1, 2015

Sorting Out Release, Uptake and Processing of Alpha-Synuclein During Prion-Like Spread of Pathology

Sorting Out Release, Uptake and Processing of Alpha-Synuclein During Prion-Like Spread of Pathology
 
Trevor Tyson, Jennifer A. Steiner and Patrik Brundin* DOI: 10.1111/jnc.13449
 
Keywords: α-synuclein; prion; homeostasis; autophagy; Parkinson's disease; Exocytosis; Endocytosis
 
Abstract
 
Parkinson's disease is a progressive neurological disorder that is characterized by the formation of intracellular protein inclusion bodies composed primarily of a misfolded and aggregated form of the protein α-synuclein. There is growing evidence that supports the prion-like hypothesis of α-synuclein progression. This hypothesis postulates that α-synuclein is a prion-like pathological agent and is responsible for the progression of Parkinson pathology in the brain. Potential misfolding or aggregation of α-synuclein that might occur in the peripheral nervous system as a result of some insult, environmental or genetic (or more likely a combination of both) that might spread into the midbrain, eventually causing degeneration of the neurons in the substantia nigra. As the diseases progresses further it is likely that α-synuclein pathology continues to spread throughout the brain, including the cortex, leading to deterioration of cognition and higher brain functions. While it is unknown why α-synuclein initially misfolds and aggregates, a great deal has been learnt about how the cell handles aberrant α-synuclein assemblies. In this review we focus on these mechanisms and discuss them in an attempt to define the role that they might play in the propagation of misfolded α-synuclein from cell-to-cell.
 
snip...
 
There is growing evidence that supports the prion-like hypothesis of α-synuclein progression. This hypothesis postulates that α-synuclein is a prion-like pathological agent and is responsible for the progression of Parkinson pathology in the brain. Potential misfolding or aggregation of α-synuclein that might occur in the peripheral nervous system as a result of some insult, environmental or genetic (or more likely a combination of both) that might spread into the midbrain, eventually causing degeneration of the neurons in the substantia nigra. As the diseases progresses further it is likely that α-synuclein pathology continues to spread throughout the brain, including the cortex, leading to deterioration of cognition and higher brain functions. While it is unknown why α-synuclein initially misfolds and aggregates, a great deal has been learnt about how the cell handles aberrant α-synuclein assemblies. In this review we focus on these mechanisms and discuss them in an attempt to define the role that they might play in the propagation of misfolded α-synuclein from cell-to-cell.
 
snip...
 
When it was found that Lewy pathology can develop in immature neurons grafted to the brains of PD patients more than one decade earlier (Kordower et al 2008, Li et al 2007), the idea that the spreading agent is a misfolded variant of α-syn was launched (Li et al 2008; Brundin et al 2008). These observations led to the formulation the prion-like hypothesis of α-syn, which postulates that misfolded α-syn is transferred between interconnected neurons and inside the new neuron it acts as a template to seed further aggregation in a prion-like manner. The hypothesis further claims that the misfolded α-syn is transported intra-axonally between brain regions where the process is repeated (George et al. 2013; Dunning et al.2011; Lema Tomé et al. 2012).
 
snip...see ;
 
 
1992 IN CONFIDENCE TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES POSSIBILITY ON A TRANSMISSIBLE PRION REMAINS OPEN
 
BSE101/1 0136
 
IN CONFIDENCE
 
CMO
 
From: . Dr J S Metiers 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 recognised 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 emphasises 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.
 
1
 
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.
 
J S METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832 llllYc!eS 2 92/11.4/1.2
 
 
>>> The only tenable public line will be that "more research is required’’ <<<
 
>>> possibility on a transmissible prion remains open<<<
 
O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ?
 
Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease
 
Received July 24, 2014; Accepted September 16, 2014; Published November 3, 2014
 
 
*** Singeltary comment PLoS ***
 
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
 
Posted by Terry S. Singeltary Sr. on 05 Nov 2014 at 21:27 GMT
 
 
Thursday, October 1, 2015
 
Alzheimergate, re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy, Singeltary Submission to Nature
 
 
Wednesday, September 2, 2015
 
Clinically Unsuspected Prion Disease Among Patients With Dementia Diagnoses in an Alzheimer’s Disease Database
 
 
March 1989
 
COMMERCIAL IN CONFIDENCE
 
INACTIVATION OF SCRAPIE-LIKE AGENTS Some implications for the use of bovine material in sterile medical devices in the UK
 
 
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 ***
 
 
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.
 
 
Tuesday, May 26, 2015
 
*** Minimise transmission risk of CJD and vCJD in healthcare settings ***
 
Last updated 15 May 2015
 
 
 
Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease
 
Received July 24, 2014; Accepted September 16, 2014; Published November 3, 2014
 
 
*** Singeltary comment PLoS Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease ***
 
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
 
*** Singeltary comment PLoS ***
 
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
 
Posted by flounder on 05 Nov 2014 at 21:27 GMT
 
 
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
 
 
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.
 
 
IN STRICT CONFIDENCE
 
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
 
 
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
 
 
snip...
 
*** Singeltary comment PLoS ***
 
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
 
Posted by flounder on 05 Nov 2014 at 21:27 GMT
 
 
 
***PRION2015 Ft. Collins***
 
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.
 
==========
 
 
 
Tuesday, June 30, 2015
 
PRION2015 Alzheimer’s disease
 
 
Tuesday, November 26, 2013
 
Transmission of multiple system atrophy prions to transgenic mice
 
 
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?
 
 
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.
 
 
iatrogenic, what if ???
 
Tuesday, September 1, 2015
 
Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism
 
 
 
Wednesday, September 2, 2015
 
Clinically Unsuspected Prion Disease Among Patients With Dementia Diagnoses in an Alzheimer’s Disease Database
 
 
 
Terry S. Singeltary Sr.
 
 

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