Transmission of amyloid lesions in Alzheimer’s disease: contributing data from animal models

Depuis la découverte du caractère transmissible des maladies à prions, d’autres protéinopathies cérébrales ont été soupçonnées d’être similairement transmissibles. La maladie d’Alzheimer (MA) est caractérisée par des dépôts cérébraux de peptides (Aβ ) et de protéines Tau hyperphosphorylées, respectivement en plaques amyloïdes et dégénérescences neurofibrillaires. Bien qu’aucune étude épidémiologique ne montre que la MA se transmette entre individus, plusieurs études ont récemment soulevé des soupçons de transmission iatrogène des dépôts β-amyloïdes chez l’Homme. Elles suggèrent que le changement de conformation (ou mépliement) de l’Aβ et son agrégation se produit par des mécanismes de nucléation-élongation et de propagation, similaires à ceux décrits pour les maladies à prions. Ici, nous présentons une revue de la littérature démontrant à partir d’études in vivo la pertinence des mécanismes de mépliement et agrégation de type prion pour la pathologie β-amyloïde.Since the discovery of the transmissibility of prion diseases, other cerebral proteinopathies have been suspected to harbor similar transmissible properties. Alzheimer’s disease (AD) is characterized by the deposition of misfolded β-amyloïdes (Aβ ) peptides and hyperphosphorylated Tau proteins, forming amyloid plaques and neurofibrillary tangles respectively in the brain. Although available epidemiological data suggest that AD is not transmitted between individuals, suspicion has recently been raised for iatrogenic β-amyloidosis transmission between humans. This suggests that A b misfolding and aggregation could occur through seeding and spreading mechanisms, virtually identical to those of prions. Here, we present a review of the literature focusing on the relevance of prion-like misfolding and aggregation mechanisms for Aβ in animal models

Small critical RNAs in the scrapie agent

Unconventional infectious agents cause transmissible spongiform encephalopathy (TSE) diseases including scrapie and bovine spongiform encephalopathy (BSE) in animals and Creutzfeldt-Jakob disease in humans. The protein only hypothesis claims that the TSE agent is composed solely of the protein called prion (PrP^sc^)^1^. This protein is the misfolded form of a host-encoded cellular protein, PrP^c^ exerting presumably a vital role at the synapse^2^. Even though now widely accepted, the prion concept fails to provide in certain circumstances^3-6^, a satisfying interpretation of the infectious phenomenon. Using the 263K scrapie-hamster model, we conducted a transmission study to search for a putative prion-associated factor indispensable for infectivity. Here we show that innocuous recombinant prion protein (recPrP) was capable, in a reproducible manner, of transmitting scrapie disease when the protein was [beta]–sheet converted in a solution containing PrP^sc^-derived RNA material. Analysis of the PrP-RNA mixture revealed the association of recPrP with two prominent populations of small RNA molecules having an average length of about ~27 and ~55 nucleotides. We conclude that the nature of the TSE agent seems to be composed of a nucleoprotein molecular complex, in which informative RNA molecules of small sizes are associated with the misfolded prion protein (PrP^sc^)

Biology of prions : from the molecular enigma to current risks

Prions are in many ways a real biological enigma, given that the exact nature of the pathogen is still unclear. Bovine Spongiform Encephalopathy (BSE) in Great-Britain, and its related disorder the variant form of Creutzfeldt-Jakob Disease (v-CJD) represent major challenges in terms of animal and human health, given the risks of food-borne contamination, and of secondary man-to-man contamination. Improved knowledge of the biology of these agents has led to major progress over the past few years, notably in the field of diagnosis, decontamination and risk analysis, thereby improving the management of these diseases.Les prions constituent par bien des points une énigme biologique. Notamment, leur nature exacte en tant qu'agent infectieux n'est pas définie précisément. L'Encéphalopathie Spongiforme Bovine (ESB) en Grande-Bretagne, et son corollaire chez l'Homme, la variante de la Maladie de Creutzfeldt-Jakob (v-MCJ), représentent des défis importants en termes de santés animale et humaine, compte tenu des risques de contaminations par voie alimentaire d'une part, et de contaminations secondaires interhumaines d'autre part. La meilleure connaissance de la biologie de ces agents a permis des avancées pratiques importantes ces dernières années, notamment en termes de diagnostic, de décontamination et d'évaluation des risques, permettant ainsi une meilleure gestion de ces maladies

Diagnostic tests for human and animal prion diseases

The potential existence of clinically silent cases of bovine spongiform encephalopathy (BSE) among cattle, and of humans incubating the new variant Creutzfeldt-Jakob disease (nvCJD) is still a major public health concern. Therefore, the development of screening tests for transmissible subacute spongiform encephalopathies (TSSE) in man and animals remains a priority. In the first part of this paper, we review the main methods used to diagnose generally clinical TSSE, such as brain imaging, electroencephalogram (EEG) analysis, and cerebrospinal fluid (CSF) analysis. In the second part, we present the post-mortem tests used to confirm a TSSE diagnosis, such as inoculation to laboratory animals, histological examination, and identification of abnormal prion protein (PrPres) using biochemical methods. Finally, the third part presents so-called rapid tests (Prionics, Bio-rad, Enfer), validated by the European Commission (EC) for post-slaughter BSE diagnosis in cattle. Now used on a large scale in Europe, these tests have helped assess the extent of the epizooty and eliminate from the food chain animals presenting a risk for human consumption. Since 2002, they have been used for the post-slaughter diagnosis of scrapie in small ruminants. New tests have recently been evaluated by the EC, but it is too soon to predict their role in the field.L'existence potentielle de bovins en phase de latence cliniquement silencieuse d'encéphalopathie spongiforme bovine (ESB) et d'individus en période d'incubation de la nouvelle variante de la maladie de Creutzfeldt-Jakob représente constamment un grand risque pour la santé publique. Par conséquent, le développement de tests de dépistage des encéphalopathies spongiformes subaiguës transmissibles (ESST) humaines et animales constitue toujours une priorité. Dans la première partie de cet article, sont décrites les principales méthodes d'orientation permettant d'aider au diagnostic d'une ESST le plus souvent clinique, comme l'imagerie médicale cérébrale, l'analyse de l'électroencéphalogramme (EEG) et l'examen du liquide céphalo-rachidien. Dans la deuxième partie, sont présentés les tests de confirmation post mortem du diagnostic des ESST, comme l'inoculation à l'animal de laboratoire, l'examen histologique et la recherche de la PrPres par des méthodes biochimiques. La troisième partie est consacrée aux tests dits « rapides » (Prionics, Bio-rad, Enfer), validés en 1999 par la Commission Européenne (CE), pour le diagnostic post mortem de l'ESB à l'abattoir chez les bovins. Utilisés à grande échelle en Europe, ils ont permis de préciser l'étendue réelle de l'épizootie et d'éliminer efficacement de la chaîne alimentaire les animaux présentant un risque pour l'homme. Depuis 2002, ils sont également utilisés pour le diagnostic post mortem des petits ruminants. De nouveaux tests ont été récemment évalués par la CE, mais il est trop tôt pour évaluer la place qu'ils tiendront sur le terrain

Encephalopathy induced by Alzheimer brain inoculation in a non-human primate.

Alzheimer's disease is characterized by cognitive alterations, cerebral atrophy and neuropathological lesions including neuronal loss, accumulation of misfolded and aggregated β-amyloid peptides (Aβ) and tau proteins. Iatrogenic induction of Aβ is suspected in patients exposed to pituitary-derived hormones, dural grafts, or surgical instruments, presumably contaminated with Aβ. Induction of Aβ and tau lesions has been demonstrated in transgenic mice after contamination with Alzheimer's disease brain homogenates, with very limited functional consequences. Unlike rodents, primates naturally express Aβ or tau under normal conditions and attempts to transmit Alzheimer pathology to primates have been made for decades. However, none of earlier studies performed any detailed functional assessments. For the first time we demonstrate long term memory and learning impairments in a non-human primate (Microcebus murinus) following intracerebral injections with Alzheimer human brain extracts. Animals inoculated with Alzheimer brain homogenates displayed progressive cognitive impairments (clinical tests assessing cognitive and motor functions), modifications of neuronal activity (detected by electroencephalography), widespread and progressive cerebral atrophy (in vivo MRI assessing cerebral volume loss using automated voxel-based analysis), neuronal loss in the hippocampus and entorhinal cortex (post mortem stereology). They displayed parenchymal and vascular Aβ depositions and tau lesions for some of them, in regions close to the inoculation sites. Although these lesions were sparse, they were never detected in control animals. Tau-positive animals had the lowest performances in a memory task and displayed the greatest neuronal loss. Our study is timely and important as it is the first one to highlight neuronal and clinical dysfunction following inoculation of Alzheimer's disease brain homogenates in a primate. Clinical signs in a chronic disease such as Alzheimer take a long time to be detectable. Documentation of clinical deterioration and/or dysfunction following intracerebral inoculations with Alzheimer human brain extracts could lead to important new insights about Alzheimer initiation processes

Atypical BSE (BASE) Transmitted from Asymptomatic Aging Cattle to a Primate

BACKGROUND: Human variant Creutzfeldt-Jakob Disease (vCJD) results from foodborne transmission of prions from slaughtered cattle with classical Bovine Spongiform Encephalopathy (cBSE). Atypical forms of BSE, which remain mostly asymptomatic in aging cattle, were recently identified at slaughterhouses throughout Europe and North America, raising a question about human susceptibility to these new prion strains. METHODOLOGY/PRINCIPAL FINDINGS: Brain homogenates from cattle with classical BSE and atypical (BASE) infections were inoculated intracerebrally into cynomolgus monkeys (Macacca fascicularis), a non-human primate model previously demonstrated to be susceptible to the original strain of cBSE. The resulting diseases were compared in terms of clinical signs, histology and biochemistry of the abnormal prion protein (PrPres). The single monkey infected with BASE had a shorter survival, and a different clinical evolution, histopathology, and prion protein (PrPres) pattern than was observed for either classical BSE or vCJD-inoculated animals. Also, the biochemical signature of PrPres in the BASE-inoculated animal was found to have a higher proteinase K sensitivity of the octa-repeat region. We found the same biochemical signature in three of four human patients with sporadic CJD and an MM type 2 PrP genotype who lived in the same country as the infected bovine. CONCLUSION/SIGNIFICANCE: Our results point to a possibly higher degree of pathogenicity of BASE than classical BSE in primates and also raise a question about a possible link to one uncommon subset of cases of apparently sporadic CJD. Thus, despite the waning epidemic of classical BSE, the occurrence of atypical strains should temper the urge to relax measures currently in place to protect public health from accidental contamination by BSE-contaminated products

CONTRIBUTION AU DEVELOPPEMENT D'UN TEST DE DIAGNOSTIC POST MORTEM DES BOVINS ATTEINTS D'ENCEPHALOPATHIE SPONGIFORME BOVINE

MAISONS-ALFORT-Ecole Vétérin (940462302) / SudocSudocFranceF

Molecular mechanisms linking Alzheimer and prion diseases-The role of aβ In PrP aggregation

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