Saturday, November 19, 2022

Aβ and tau prions feature in the neuropathogenesis of Down syndrome

SATURDAY, NOVEMBER 19, 2022

Aβ and tau prions feature in the neuropathogenesis of Down syndrome

Aβ and tau prions feature in the neuropathogenesis of Down syndrome

Carlo Condello carlo.condello@ucsf.edu, Alison M. Maxwell, Erika Castillo https://orcid.org/0000-0003-2492-901X, +9, and Stanley B. Prusiner 


stanley.prusiner@ucsf.eduAuthors Info & Affiliations

Contributed by Stanley Prusiner; received August 1, 2022; accepted September 27, 2022; reviewed by Robert Brown Jr. and Neil Cashman.

November 7, 2022

119 (46) e2212954119


Significance

Approximately 5.4 million people worldwide have Down syndrome (DS), which is caused by trisomy of chromosome 21 (Chr21). The APP gene is one of approximately 250 protein-coding genes located on Chr21, and its duplication is associated with elevated Aβ production and increased incidence of Alzheimer’s disease (AD) neuropathology in most aged individuals with DS. Since AD brains have plaques composed of Aβ prions and neurofibrillary tangles composed of tau prions, we asked if DS brains have both Aβ and tau prions. We found that the age-dependent kinetics of Aβ and tau prions are distinct in DS and could even be detected in a 19-y-old individual. Whether DS is an ideal model for assessing efficacy of putative AD therapeutics remains unknown.

Abstract

Down syndrome (DS) is caused by the triplication of chromosome 21 and is the most common chromosomal disorder in humans. Those individuals with DS who live beyond age 40 y develop a progressive dementia that is similar to Alzheimer’s disease (AD). Both DS and AD brains exhibit numerous extracellular amyloid plaques composed of Aβ and intracellular neurofibrillary tangles composed of tau. Since AD is a double-prion disorder, we asked if both Aβ and tau prions feature in DS. Frozen brains from people with DS, familial AD (fAD), sporadic AD (sAD), and age-matched controls were procured from brain biorepositories. We selectively precipitated Aβ and tau prions from DS brain homogenates and measured the number of prions using cellular bioassays. In brain extracts from 28 deceased donors with DS, ranging in age from 19 to 65 y, we found nearly all DS brains had readily measurable levels of Aβ and tau prions. In a cross-sectional analysis of DS donor age at death, we found that the levels of Aβ and tau prions increased with age. In contrast to DS brains, the levels of Aβ and tau prions in the brains of 37 fAD and sAD donors decreased as a function of age at death. Whether DS is an ideal model for assessing the efficacy of putative AD therapeutics remains to be determined.

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Discussion

Our findings demonstrate that the brains of people with DS feature both Aβ and tau prions, which appear to be indistinguishable from the two prions that accumulate in both the sporadic and familial forms of AD. Importantly, DS is neither sporadic nor inherited, but it is a genetic disease caused by complete or partial triplication of Chr21. In trisomic individuals who bear an extra copy of the APP gene, the overexpression of wild-type (WT) APP results in increased levels of Aβ prions. Conversely, partial trisomy lacking triplication of APP does not lead to the neuropathologic changes of AD (50, 51). While we have previously reported that Aβ prions in the absence of tau prions result in cerebral amyloid angiopathy (26), this is not the case for DS. We found both Aβ and tau prions in nearly all of the brains of our DS cohort. In agreement with others, we propose that research in people with DS may help clarify sAD pathogenesis, given that both neuropathology and prion infectivity closely resemble that found in sAD, the predominant form of AD.

Notably, some individuals with DS exhibit many co-occurring conditions, including heart defects, obesity, diabetes, and progeria. How these conditions in people with DS modify the central nervous system dysfunction in the aging DS brain is unclear. There is evidence from mouse models that triplication of some Chr21 homologs increases Aβ deposition independently of an extra APP copy (52); conversely, APP duplication alone is sufficient to cause AD (53). APP duplications in DS provide an interesting comparison to Tg(APP) mice, which also overexpress human APP and Aβ. However, we note that plaques only form in Tg mice bearing familial mutations in APP and not WT APP; efforts to knock-in the WT human APP allele or humanize the Aβ peptide sequence within rodent App do not lead to plaque formation in the lifespan of a mouse (54, 55). Moreover, while the first generation of DS mouse models, segmental trisomy of mouse Chr16 (e.g., Ts65Dn) (56, 57), do replicate many neurodevelopmental phenotypes and present age-related neurodegeneration, they do not produce robust Aβ pathology in aged mice (58). One caveat of the Ts65Dn model is that it duplicates genes not present on human Chr21. To avoid this, new models employing transchromosomic (Tc) techniques in mice and rats have been developed in which the long arm of human Chr21 is cloned into the rodent genome. Despite this advancement, there is still a lack of Aβ plaque formation during the Tc(Chr21) rodent lifespan (59, 60). Whether or not Aβ prions could be measured in Tc(Chr21) rodents using cellular bioassays remains to be determined. Nevertheless, these findings suggest that the formation of Aβ and tau prions as well as AD neuropathology resulting from overexpression of WT human APP is a uniquely human condition. These findings make it critical to use human brain samples wherever possible to investigate the molecular pathogenesis of DS.

Effects of Aβ concentration on the formation of Aβ prion strains may be amenable to study in both rodents and humans. In prior work, we demonstrated that the brain concentrations of APP, Aβ40, and Aβ42 proteins in long-lived people with AD trended significantly lower (P < 0.005) compared with people who died much younger (26). This matches the lower Aβ prion infectivity observed with cell bioassays in those same people (26). If such a trend was present from a young age, it might indicate that low APP expression over the lifespan contributes to an Aβ prion strain that is less pathogenic or slower to accumulate and contributes to longevity. Interestingly, using amyloid strain-sensitive dyes and spectral imaging methods in fixed tissues (61), we found that the conformation of Aβ plaques in aged individuals with DS and advanced neuropathology showed a distinct conformational strain phenotype, compared with sAD (62). While the relationship between amyloid plaque conformation and Aβ prion infectivity remains to be determined, there is growing evidence that supports the notion that pathogenic Aβ and tau species in DS may differ from fAD and sAD in ways not appreciated with traditional histological and biochemical measurements.

Our prion bioassays allow for measurement of both Aβ and tau prions in DS rather than inert protein deposits. The finding that Aβ and tau prions are positively correlated in DS and AD agrees well with genetic and experimental studies arguing that Aβ prions arise early in AD pathogenesis and that these prions initiate subsequent tau prion formation (63–65). Consistent with this notion, we found that samples from two of the youngest individuals with DS in our study (19 and 25 y old) exhibited robust levels of Aβ prions but insignificant levels of tau prions; in adjacent formalin-fixed sections, we found that these donors had low levels of plaques and tangles (SI Appendix, Fig. S2). In contrast, we have not found any brains with DS or AD that have readily detectable levels of tau prions accompanied by marginal levels of Aβ prions. Indeed, our studies of primary tauopathies such as progressive supranuclear palsy and corticobasal degeneration have failed to show any detectable Aβ prions (26). To our knowledge, individuals with DS do not present with only NFTs in the absence of amyloid plaques (15). This finding is consistent with our view that Aβ prions initiate formation of tau NFTs in the vast majority of people with AD as well as DS.

Indeed, the cellular bioassays provide a functional readout of self-replicative proteins but do not provide the biophysical or structural characteristics of a given prion. It will be important for future mechanistic and drug discovery research to more precisely understand the molecular features of Aβ and tau prions in DS and AD. For example, Aβ peptides assemble into aggregates, which are called oligomers when the aggregate size is less than ∼50 peptides (66). A multitude of studies on human brain samples have reported the existence of soluble Aβ oligomers ranging in size, including dimers, trimers, and tetramers (67). Oligomer size has also been found to correlate inversely with cellular toxicity (68, 69). Moreover, the abundance of Aβ oligomers correlates well with the progression of cognitive deficits (70–72) and can differentiate patients with AD from nondemented people with comparable amyloid plaque burden (73). Extensive studies of Aβ oligomers in DS are lacking, but a few reports indicate an early (preplaque accumulation) and persistent increase of Aβ oligomers in aging DS people (74, 75). This is consistent with our data showing abundant Aβ prions in young people with DS with little to no amyloid plaque pathology. To our knowledge, there are no reports describing the characterization of tau oligomers in the brains of DS donors. Whether Aβ or tau multimer size correlates with prion infectivity and pathological deposition remains to be determined. By quantifying the oligomeric distribution and concentration, it should be possible to establish a relationship between the number of proteins in an oligomer and its prion infectivity (i.e., the particle to infectivity ratio [P/I]). For example, the P/I is ∼5,000 for the scrapie PrP isoform (76).

DS reveals a new vista of prion biology where trisomy of Chr21 results in increased Aβ production from an early age and leads to the formation of Aβ prions (77–80). It will be important to determine if this phenomenon occurs in all people with DS or a subset and to establish the earliest ages of prion detection. Despite the extraordinary contrast in etiologies between two genetic forms of Aβ prion diseases, one of which is nonheritable (DS) and the other heritable (fAD), both DS and fAD lead to a convergent neuropathogenic phenotype. Notably, by including sAD with fAD and DS, these three double-prion diseases are the most frequent neurodegenerative conditions worldwide, in which Aβ prions stimulate tau prions to cause neurodegeneration. Moreover, DS joins the expanding spectrum of NDs known to be caused by pathogenic prions (Table 1). Indeed, PrP prions cause Creutzfeldt-Jakob disease and kuru and can manifest in sporadic, heritable, and communicable disorders. While the other NDs can be sporadic or heritable, there is little evidence that Aβ, tau, or α-synuclein prions are communicable or spread by iatrogenic transmission (102–105). However, Aβ, tau, or α-synuclein prions extracted from donor brains of each disease can be transmitted to experimental animals or cultured human cells. These transmission models have enabled investigations of prion disease mechanisms and preclinical testing of novel therapeutic candidates.

Ridley et al. (34) provided the first clues of Aβ prions in the brains of people with DS, but the incubation times in marmosets are much too long for experimental investigations. In contrast, using our rapid cell bioassays, we discovered that the brains of people with DS contain both Aβ and tau prions indistinguishable from those found in AD. Our findings offer an approach to comparative clinical studies of AD and DS. As we learn more about Aβ and tau prions in DS, it may be feasible to develop smaller, shorter, and more informative clinical trials of potential AD treatments (106, 107). Whether advances in human positron emission tomography imaging for both Aβ plaques and NFTs will prove useful in assessing the levels of Aβ and tau prions in the brains of adults with DS who receive putative anti–AD prion therapeutics remains to be established. Last, because the brains of long-lived people with DS exhibit increased prion infectivity, we posit that more molecular studies for people with DS are needed to better understand how age-dependent pathogenic mechanisms in DS cause a divergent prion phenotype from sAD. The outcome of such work may have important implications for developing drugs that are more aptly tailored to improve quality of life for people with DS.

snip...see full text;



Prion 2022 Conference abstracts: pushing the boundaries






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Friday, November 18, 2022

Different Aβ43 deposition patterns in the brains of aged dogs, sea lions, and cats

Different Aβ43 deposition patterns in the brains of aged dogs, sea lions, and cats

Kei TAKAHASHI1), James K CHAMBERS1)*, Yuta TAKAICHI1), Kazuyuki UCHIDA1)
1)Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Science, The University of Tokyo, Tokyo, Japan
                    
ABSTRACT. Cerebral amyloid β (Aβ) deposition is a pathological hallmark of Alzheimer’s disease (AD). There are several molecular species of Aβ, including Aβ40, Aβ42, and Aβ43, and the pathological roles of Aβ43 have attracted particular attention in recent years. Aβ43 is mainly deposited as senile plaques (SPs) in AD brains, and is known to be more amyloidogenic and neurotoxic than Aβ42 and Aβ40. Aβ40 and Aβ42 deposition have been demonstrated in several animal species, while Aβ43 deposition has not been studied in animals. The brains of sea lions, dogs, and cats exhibit unique age-related Aβ pathologies. In the present study, the deposition patterns of Aβ40, Aβ42, and Aβ43 were examined immunohistochemically in the brains of aged dogs (n=52), sea lions (n=5), and cats (n=17). In dogs, most cerebral amyloid angiopathy (CAA) lesions and primitive SPs were positive for Aβ42, Aβ43, and Aβ40. However, diffuse SPs and capillary CAA lesions were negative for Aβ40. In sea lions, all SPs and most CAA lesions were positive for Aβ42, Aβ43, and Aβ40, while capillary CAA lesions were negative for Aβ40. In cats, Aβ42-immunopositive granular aggregates and arteriole and capillary CAA lesions were positive for Aβ43, but negative for Aβ40. Double-labelling immunohistochemistry revealed the co-localization of Aβ42 and Aβ43. These findings suggest that Aβ43 and Aβ42 are frequently deposited in the brains of Carnivora animals and may play an important role in Aβ pathology.

Snip..

DISCUSSION

Parenchymal and vascular Aβ40 and Aβ42 deposits have been reported in various animal species. Conversely, an aged gorilla is the only animal that has been reported to exhibit Aβ43 deposition in its brain [27]. In this study, Aβ43 deposition in Carnivora brains was examined and compared with Aβ40 and Aβ42 deposition.

Previous studies have shown that capillary CAA (CAA-type1) is frequently seen in the canine brain [30]. The present study revealed that Aβ43 is deposited in the small arteries and capillaries in the canine brain, as is the case for Aβ42. In dogs, diffuse plaques were weakly immunopositive for Aβ43, and primitive plaques were strongly immunopositive for Aβ43. A previous study showed that canine primitive plaques contain several capillaries and may be CAA-type1-related lesions caused by the fusion of capillary CAA lesions with perivascular Aβ deposits [44]. In humans, a type of amyloid plaque called coarse-grained plaques contain vascular components (laminin, collagen IV, and norrin) and are reported to be associated with CAA-type1 [5]. The canine primitive plaques examined in the present study also contained capillaries and were located adjacent to capillary CAA lesions with dispersed Aβ aggregates called dysphoric capillary CAA lesions [34]. These findings suggest that Aβ43 deposition in dogs is associated with CAA-type1 and has different properties from the Aβ42 deposition associated with SP formation.

Two types of SP (mature and diffuse plaques) and CAA have been reported in aged sea lion brains [40, 41]. The present study showed that Aβ43 was frequently deposited in small arteries and capillaries in sea lion brains, as was seen in the canine brains. On the other hand, Aβ43 positive plaques were found more frequently in sea lion brains than in canine brains. In human AD and transgenic mouse brains, Aβ43 has been found in diffuse and mature (dense-cored) plaques, and Aβ43 was localized in plaque cores [21, 37]. The current study revealed that Aβ43 was present in the cores of mature plaques in sea lion brains. These findings suggest that in sea lions Aβ43 is associated with both CAA-type1 and plaque formation. Thus, different Aβ43 deposition patterns were observed in dogs and sea lions.

Aged cats show no SPs but exhibit small granular deposits of Aβ and few CAA [11, 15, 28]. This deposition pattern is thought to be associated with the 7th amino acid substitution of feline Aβ amino acid sequence compared to that of humans, dogs, and sea lions which exhibit SPs [6, 22, 41]. The present study revealed that Aβ43 aggregated to form granular deposits and cortical CAA lesions, which was similar to the deposition pattern of Aβ42 in the feline brain. The aggregation properties of the various Aβ subtypes differ, and Aβ43 has the strongest propensity to aggregate, followed by Aβ42 and Aβ40 [37]. The deposition pattern of Aβ is also affected by the subtype (Aβ43: plaques, Aβ42: plaques and CAA, Aβ40: CAA) [21]. In the present study, there was no significant difference between the Aβ43 and Aβ42 deposition scores for the feline brains. These results imply that Aβ43 and Aβ42 exhibit similar Aβ aggregation behavior in the feline brain.

The Aβ in meningeal and arterial CAA is predominantly composed of Aβ40 [17, 23], but capillary CAA is characterized by Aβ42 deposits [2]. In the present study, Aβ43 was frequently deposited in capillary and arteriole walls, as was found for Aβ42 deposition in dog and sea lion brains. Aβ40 was mainly deposited in larger CAA-affected blood vessels and absent from capillary CAA lesions in dogs and sea lions. The intramural periarterial drainage (IPAD) pathway is the perivascular clearance pathway through which interstitial fluid containing Aβ accumulates around capillaries and leaves the brain between the smooth muscle cell basement membranes in the tunica media of arterioles and arteries [3, 8]. CAA is considered to be strongly associated with the IPAD pathway since the observed Aβ accumulation patterns are consistent with this pathway [48]. Aβ40, a comparatively soluble subtype of Aβ, can diffuse along perivascular drainage pathways and accumulate in the smooth muscle cell basement membranes of arterioles and meningeal blood vessels, which are located downstream of the IPAD pathway [25]. On the other hand, Aβ42 mainly accumulates in capillaries, which are located upstream of the IPAD pathway because of their strong propensity to aggregate [2]. Accordingly, our findings suggested that Aβ43 is mainly deposited upstream of the IPAD pathway in dog and sea lion brains, possibly because Aβ43 has a stronger propensity to aggregate than Aβ42 [37].

In the human brain, Aβ43 mainly accumulates as SPs, and it accumulates as CAA lesions less often [47]. In the present study, Aβ43 mainly accumulated as cortical CAA lesions and accumulated less often as SPs in the brains of dogs and sea lions. An in vitro study found that the toxicity of Aβ to human cerebrovascular cells (smooth muscle cells and brain pericytes) decreases in the following order: Aβ40 >Aβ42 >Aβ43 [20]. Furthermore, the propensity of Aβ species to form CAA lesions follows the same order [21]. The smooth muscle cells in the tunica media are involved in the IPAD pathway [26], and Jäkel et al. suggested that the lower vulnerability of human smooth muscle cells to Aβ43 may be associated with less Aβ43 deposition occurring in the blood vessel walls in the human brain because of Aβ43 having less toxic effects on the IPAD pathway. In the present study, a different correlation between peptide length and cortical CAA formation (Aβ40 <Aβ42 ≈Aβ43) was seen in the Caniformia brains than has been observed in human brains. The vulnerability of Caniformia (dog and sea lion) cerebrovascular smooth muscle cells to Aβ may differ from that of human cerebrovascular smooth muscle cells.

A previous study showed that Aβ43 accumulates more frequently than Aβ40 in the brains of AD patients [37]. The present study revealed that Aβ43 was deposited as SPs and CAA lesions in Carnivora brains, and the Aβ43 deposition scores of these brains were higher than their Aβ40 deposition scores. This indicated that Aβ43 is one of the major components of Aβ pathology in the Carnivora brain. Furthermore, the co-localization of Aβ43 and Aβ42 was confirmed by double-labeling immunohistochemistry in the animal brains. It is known that Aβ43 exhibits significant seeding activity and induces Aβ42 aggregation [36]. The present study suggests that Aβ43 plays a vital role in Aβ pathology by being associated with Aβ42 deposition in the Carnivora brain.

KEYWORDS: Aβ43, Carnivora, cerebral amyloid angiopathy, senile plaque


for me, this brings up the topic of TSE Prion disease. we know feline spongiform encephalopathy has been documented, but canine spongiform encephalopathy, to date, has not been documented, or maybe it has, but how many of these animals are ever tested for TSE Prion in the USA? they really have not a clue as to any canine spongiform encephalopathy, FSE, i have never heard of any being tested in the USA for any TSE. i remember the hound survey during the early days of the BSE, about the time that FSE broke out. but they did not further investigate those canine brains that were suspicious looking. why? 

with the total failure of the mad cow feed ban in the USA, new outbreak of a new livestock Prion disease in Camels in two Countries, we must start looking for TSE Prion disease in these species. 

Also, not to forget, aged cattle brains displays Alzheimer's Disease-Like pathology and promotes Brain Amyloidosis in a Transgenic Animal Model. transmissible??? what about feed??? see;

Aged Cattle Brain Displays Alzheimer's Disease-Like Pathology and Promotes Brain Amyloidosis in a Transgenic Animal Model 

Front. Aging Neurosci., 31 January 2022 | https://doi.org/10.3389/fnagi.2021.815361

Aged Cattle Brain Displays Alzheimer's Disease-Like Pathology and Promotes Brain Amyloidosis in a Transgenic Animal Model

Ines Moreno-Gonzalez1,2,3,4*, George Edwards III1, Rodrigo Morales1,4, Claudia Duran-Aniotz1,5,6, Gabriel Escobedo Jr.1, Mercedes Marquez7, Marti Pumarola7,8 and Claudio Soto1*

1Department of Neurology, Mitchell Center for Alzheimer's Disease and Related Brain Disorders, University of Texas Health Science Center at Houston, Houston, TX, United States

2Departamento Biología Celular, Genética y Fisiología, Instituto de Investigacion Biomedica de Malaga-IBIMA, Universidad de Malaga, Malaga, Spain

3Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain

4Centro Integrativo de Biologia y Quimica Aplicada (CIBQA), Universidad Bernardo O'Higgins, Santiago, Chile

5Center for Social and Cognitive Neuroscience (CSCN), School of Psychology, Universidad Adolfo Ibáñez, Santiago, Chile

6Latin American Institute for Brain Health (BrainLat), Universidad Adolfo Ibanez, Santiago, Chile

7Department of Animal Medicine and Surgery, Veterinary Faculty, Animal Tissue Bank of Catalunya (BTAC), Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Valles), Barcelona, Spain

8Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Universitat Autonoma de Barcelona, Bellaterra (Cerdanyola del Valles), Barcelona, Spain

Alzheimer's disease (AD) is one of the leading causes of dementia in late life. Although the cause of AD neurodegenerative changes is not fully understood, extensive evidence suggests that the misfolding, aggregation and cerebral accumulation of amyloid beta (Aβ) and tau proteins are hallmark events. Recent reports have shown that protein misfolding and aggregation can be induced by administration of small quantities of preformed aggregates, following a similar principle by which prion diseases can be transmitted by infection. In the past few years, many of the typical properties that characterize prions as infectious agents were also shown in Aβ aggregates. Interestingly, prion diseases affect not only humans, but also various species of mammals, and it has been demonstrated that infectious prions present in animal tissues, particularly cattle affected by bovine spongiform encephalopathy (BSE), can infect humans. It has been reported that protein deposits resembling Aβ amyloid plaques are present in the brain of several aged non-human mammals, including monkeys, bears, dogs, and cheetahs. In this study, we investigated the presence of Aβ aggregates in the brain of aged cattle, their similarities with the protein deposits observed in AD patients, and their capability to promote AD pathological features when intracerebrally inoculated into transgenic animal models of AD. Our data show that aged cattle can develop AD-like neuropathological abnormalities, including amyloid plaques, as studied histologically. Importantly, cow-derived aggregates accelerate Aβ amyloid deposition in the brain of AD transgenic animals. Surprisingly, the rate of induction produced by administration of the cattle material was substantially higher than induction produced by injection of similar amounts of human AD material. Our findings demonstrate that cows develop seeding-competent Aβ aggregates, similarly as observed in AD patients.

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The prion-like transmission of Aβ aggregates has been extensively reported in animal models and likely plays an important role in the progressive spreading of pathological abnormalities throughout the brain (Moreno-Gonzalez and Soto, 2011; Thal et al., 2014; Walker and Jucker, 2015). Nevertheless, whether this phenomenon ever operates in the inter-individual transmission of disease pathology in humans remains highly debatable. Recent studies have provided evidence for the induction of Aβ aggregation in people receiving human pituitary-derived growth hormone (Jaunmuktane et al., 2015; Ritchie et al., 2017). However, when the risk of AD development, and not only amyloid pathology, was studied no evidence was found for disease transmission (Irwin et al., 2013). The findings of our current study suggest that Aβ aggregates present in the brains of old cattle are competent to seed amyloid deposition in vivo. This induction has also been observed with other protein aggregates such as AA amyloid (Rising et al., 2021). However, the potential transmission of Aβ cattle-derived seeds to humans is unlikely, considering that repeated oral administration of AD brain extracts to susceptible mice failed to accelerate pathological features (Morales et al., 2021). The results presented in this manuscript suggest that aged cattle are susceptible to develop pathological features similar to AD, and that misfolded Aβ present in their brain is seeding competent.


P1-187 AGED CATTLE BRAIN DISPLAYSALZHEIMER’S-LIKE PATHOLOGY THATCAN BE PROPAGATED IN A PRION-LIKE MANNER

Ines Moreno-Gonzalez1, George A. Edwards, III,1, Nazaret Gamez Ruiz1,Priyadarshini Peter1, Rodrigo Morales1, Mercedes Marquez2, Marti Pumarola2,Claudio Soto1,1The University of Texas Health Science Center at Houston, Houston, TX, USA;2Animal Tissue Bank of Catalunya (BT A C), Universidad Autonoma de Barcelona, Barcelona, Spain . Contact e-mail: Ines.M.Gonzalez@uth.tmc.edu

Background: Amyloid beta (Ab) and hyperphosphorylated tau(ptau) are the proteins undergoing misfolding in Alzheimer’s dis-ease (AD). Recent studies have shown that brain homogenates rich in amyloid aggregates are able to seed the misfolding and ag-gregation of amyloidogenic proteins inducing an earlier onset of the disease in mouse models of AD. This seeding behavior is analogous to the disease transmission by propagation of prion protein misfold-ing observed in prion diseases. Prion diseases can be transmitted across species by inoculation of the misfolded prion protein from one specie into an appropriate host. For example, material from cattle affected by bovine spongiform encephalopathy can be propagate in humans inducing variant Creutzfeldt-Jakob disease.

Methods: In this study, we analyzed the presence of AD-related protein aggre-gates in the brain of old cows and investigated whether these aggregates are capable to induce pathology in animal models of AD.

Results: We observed that many of the typical hallmarks detected in human AD brains, including Ab aggregates and tangles, were present in cow brains. When cattle tissue containing Ab aggregates or ptau were intracerebrally inoculated into APP/PS1 or P301Smice, we observed an acceleration of brain misfolded protein deposition and faster cognitive impairment compared to controls. How-ever, when the material was orally inoculated, no effect was observed.

Conclusions: These results may contribute to uncover a previously unsuspected etiology surrounding some cases of spo-radic AD. However, the early and controversial stage of the field of prion-like transmission in non-prion diseases added to the artificial nature of the animal models utilized for these studies, indicate that extrapolation of the results to humans should not be done without further experiments.


P75 Determining transmissibility and proteome changes associated with abnormal bovine prionopathy 

Dudas S (1,2), Seuberlich T (3), Czub S (1,2) 

In prion diseases, it is believed that altered protein conformation encodes for different pathogenic strains. Currently 3 different strains of bovine spongiform encephalopathy (BSE) are confirmed. Diagnostic tests for BSE are able to identify animals infected with all 3 strains, however, several diagnostic laboratories have reported samples with inconclusive results which are challenging to classify. It was suggested that these may be novel strains of BSE; to determine transmissibility, brain material from index cases were inoculated into cattle. 

In the first passage, cattle were intra-cranially challenged with brain homogenate from 2 Swiss animals with abnormal prionopathy. The challenged cattle incubated for 3 years and were euthanized with no clinical signs of neurologic disease. Animals were negative when tested on validated diagnostic tests but several research methods demonstrated changes in the prion conformation in these cattle, including density gradient centrifugation and immunohistochemistry. Currently, samples from the P1 animals are being tested for changes in protein levels using 2-D Fluorescence Difference Gel Electrophoresis (2D DIGE) and mass spectrometry. It is anticipated that, if a prionopathy is present, this approach should identify pathways and targets to decipher the source of altered protein conformation. In addition, a second set of cattle have been challenged with brain material from the first passage. Ideally, these cattle will be given a sufficient incubation period to provide a definitive answer to the question of transmissibility. 

=====prion 2018=== 


Prion Conference 2018

Sunday, February 25, 2018 

PRION ROUND TABLE CONFERENCE 2018 MAY, 22-25 A REVIEW


EP-021 Canine Prions: A New Form of Prion Disease

Mourad Tayebi1, Monique A David2, Brian Summers3

1 University of Melbourne, Veterinary Sciences, Australia; 2Ausbiologics, Sydney, Australia; 3Royal Veterinary College, London, UK

The origin of bovine spongiform encephalopathy (BSE), which rapidly evolved into a major epidemic remains unresolved and was initially widely attributed to transmission of sheep scrapie to cattle with contaminated feed prepared from rendered sheep carcasses. Alternative transmission hypotheses also include feed contaminated with unrecognized subclinical case(s) of bovine prion disease or with prion-infected human remains. However, following the demonstration of a BSE case exhibiting the novel mutation E211 K, similar to the E200K mutation associated with most genetic CJD in humans, support for a genetic origin of prion disease in cattle is gaining momentum. In contrast to other animal species such as feline, the canine species seems to be resistant to prion disease as no canine prion cases were previously reported.

We describe here three cases of Rottweiler puppy (called RWD cases) with neurological deficits and spongiform change. We used animal bioassays and in vitro studies to show efficient interspecies transmission of this novel canidae prion isolate to other species.

Biochemical studies revealed the presence of partially proteinase K (PK)-resistant fragment and immunohistochemistry displayed staining for PrPSc in the cerebral cortex. Importantly, interspecies transmission of canine PrPSc derived from RWD3 brain homogenates following inoculation of hamsters led to signs of prion disease and replication of PrPSc in brains, spinal cords and spleens of these animals.

These findings if confirmed by further cases of prion disease in canidae and regardless of the origin of the disease would have a major impact on animal and public health.

PRION 2016 TOKYO



OR-09: Canine spongiform encephalopathy—A new form of animal prion disease

Monique David, Mourad Tayebi UT Health; Houston, TX USA

It was also hypothesized that BSE might have originated from an unrecognized sporadic or genetic case of bovine prion disease incorporated into cattle feed or even cattle feed contaminated with prion-infected human remains.1 However, strong support for a genetic origin of BSE has recently been demonstrated in an H-type BSE case exhibiting the novel mutation E211K.2 Furthermore, a specific prion protein strain causing BSE in cattle is believed to be the etiological agent responsible for the novel human prion disease, variant Creutzfeldt-Jakob disease (vCJD).3 Cases of vCJD have been identified in a number countries, including France, Italy, Ireland, the Netherlands, Canada, Japan, US and the UK with the largest number of cases. Naturally occurring feline spongiform encephalopathy of domestic cats4 and spongiform encephalopathies of a number of zoo animals so-called exotic ungulate encephalopathies5,6 are also recognized as animal prion diseases, and are thought to have resulted from the same BSE-contaminated food given to cattle and humans, although and at least in some of these cases, a sporadic and/or genetic etiology cannot be ruled out. The canine species seems to display resistance to prion disease and no single case has so far been reported.7,8 Here, we describe a case of a 9 week old male Rottweiler puppy presenting neurological deficits; and histological examination revealed spongiform vacuolation characteristic of those associated with prion diseases.9 Initial biochemical studies using anti-PrP antibodies revealed the presence of partially proteinase K-resistant fragment by western blotting. Furthermore, immunohistochemistry revealed spongiform degeneration consistent with those found in prion disease and displayed staining for PrPSc in the cortex.

Of major importance, PrPSc isolated from the Rottweiler was able to cross the species barrier transmitted to hamster in vitro with PMCA and in vivo (one hamster out of 5). Futhermore, second in vivo passage to hamsters, led to 100% attack rate (n = 4) and animals displayed untypical lesional profile and shorter incubation period.

In this study, we show that the canine species might be sensitive to prion disease and that PrPSc isolated from a dog can be transmitted to dogs and hamsters in vitro using PMCA and in vivo to hamsters.

If our preliminary results are confirmed, the proposal will have a major impact on animal and public health and would certainly lead to implementing new control measures for ‘canine spongiform encephalopathy’ (CSE).

References

1. Colchester AC, Colchester NT. The origin of bovine spongiform encephalopathy: the human prion disease hypothesis. Lancet 2005; 366:856-61; PMID:16139661; http:// dx.doi.org/10.1016/S0140-6736(05)67218-2.

2. Richt JA, Hall SM. BSE case associated with prion protein gene mutation. PLoS Pathog 2008; 4:e1000156; PMID:18787697; http://dx.doi.org/10.1371/journal. ppat.1000156.

3. Collinge J. Human prion diseases and bovine spongiform encephalopathy (BSE). Hum Mol Genet 1997; 6:1699-705; PMID:9300662; http://dx.doi.org/10.1093/ hmg/6.10.1699.

4. Wyatt JM, Pearson GR, Smerdon TN, Gruffydd-Jones TJ, Wells GA, Wilesmith JW. Naturally occurring scrapie-like spongiform encephalopathy in five domestic cats. Vet Rec 1991; 129:233-6; PMID:1957458; http://dx.doi.org/10.1136/vr.129.11.233.

5. Jeffrey M, Wells GA. Spongiform encephalopathy in a nyala (Tragelaphus angasi). Vet Pathol 1988; 25:398-9; PMID:3232315; http://dx.doi.org/10.1177/030098588802500514.

6. Kirkwood JK, Wells GA, Wilesmith JW, Cunningham AA, Jackson SI. Spongiform encephalopathy in an arabian oryx (Oryx leucoryx) and a greater kudu (Tragelaphus strepsiceros). Vet Rec 1990; 127:418-20; PMID:2264242.

7. Bartz JC, McKenzie DI, Bessen RA, Marsh RF, Aiken JM. Transmissible mink encephalopathy species barrier effect between ferret and mink: PrP gene and protein analysis. J Gen Virol 1994; 75:2947-53; PMID:7964604; http://dx.doi.org/10.1099/0022-1317- 75-11-2947.

8. Lysek DA, Schorn C, Nivon LG, Esteve-Moya V, Christen B, Calzolai L, et al. Prion protein NMR structures of cats, dogs, pigs, and sheep. Proc Natl Acad Sci U S A 2005; 102:640-5; PMID:15647367; http://dx.doi.org/10.1073/pnas.0408937102.

9. Budka H. Neuropathology of prion diseases. Br Med Bull 2003; 66:121-30; PMID:14522854; http://dx.doi.org/10.1093/bmb/66.1.121.


*** DEFRA TO SINGELTARY ON HOUND STUDY AND BSE 2001 ***

DEFRA Department for Environment, Food & Rural Affairs

Area 307, London, SW1P 4PQ Telephone: 0207 904 6000 Direct line: 0207 904 6287 E-mail: h.mcdonagh.defra.gsi.gov.uk

GTN: FAX:

Mr T S Singeltary P.O. Box 42 Bacliff Texas USA 77518

21 November 2001

Dear Mr Singeltary

TSE IN HOUNDS

Thank you for e-mail regarding the hounds survey. I am sorry for the long delay in responding. As you note, the hound survey remains unpublished. However the Spongiform Encephalopathy Advisory Committee (SEAC), the UK Government's independent Advisory Committee on all aspects related to BSE-like disease, gave the hound study detailed consideration at their meeting in January 1994. As a summary of this meeting published in the BSE inquiry noted, the Committee were clearly concerned about the work that had been carried out, concluding that there had clearly been problems with it, particularly the control on the histology, and that it was more or less inconclusive. However was agreed that there should be a re-evaluation of the pathological material in the study. Later, at their meeting in June 95, The Committee re-evaluated the hound study to see if any useful results could be gained from it. The Chairman concluded that there were varying opinions within the Committee on further work. It did not suggest any further transmission studies and thought that the lack of clinical data was a major weakness.

Overall, it is clear that SEAC had major concerns about the survey as conducted. As a result it is likely that the authors felt that it would not stand up to r~eer review and hence it was never published. As noted above, and in the detailed minutes of the SEAC meeting in June 95, SEAC considered whether additional work should be performed to examine dogs for evidence of TSE infection. Although the Committee had mixed views about the merits of conducting further work, the Chairman noted that when the Southwood Committee made their recommendation to complete an assessment of possible spongiform disease in dogs, no TSEs had been identified in other species and hence dogs were perceived as a high risk population and worthy of study. However subsequent to the original recommendation, made in 1990, a number of other species had been identified with TSE ( e.g. cats) so a study in hounds was less

critical. For more details see- http://www.bseinquiry.gov.uk/files/yb/1995/06/21005001.pdf As this study remains unpublished, my understanding is that the ownership of the data essentially remains with the original researchers. Thus unfortunately, I am unable to help with your request to supply information on the hound survey directly. My only suggestion is that you contact one of the researchers originally involved in the project, such as Gerald Wells. He can be contacted at the following address.

Dr Gerald Wells, Veterinary Laboratories Agency, New Haw, Addlestone, Surrey, KT 15 3NB, UK You may also wish to be aware that since November 1994 all suspected cases of spongiform encephalopathy in animals and poultry were made notifiable. Hence since that date there has been a requirement for vets to report any suspect SE in dogs for further investigation. To date there has never been positive identification of a TSE in a dog.

I hope this is helpful

Yours sincerely 4

HUGH MCDONAGH BSE CORRESPONDENCE SECTION

======================================

HOUND SURVEY

I am sorry, but I really could have been a co-signatory of Gerald's minute.

I do NOT think that we can justify devoting any resources to this study, especially as larger and more important projects such as the pathogenesis study will be quite demanding.

If there is a POLITICAL need to continue with the examination of hound brains then it should be passed entirely to the VI Service.

J W WILESMITH Epidemiology Unit 18 October 1991

Mr. R Bradley

cc: Mr. G A H Wells


3.3. Mr R J Higgins in conjunction with Mr G A Wells and Mr A C Scott would by the end of the year, indentify the three brains that were from the ''POSITIVE'' end of the lesion spectrum.


TSE in dogs have not been documented simply because OF THE ONLY STUDY, those brain tissue samples were screwed up too. see my investigation of this here, and to follow, later follow up, a letter from defra, AND SEE SUSPICIOUS BRAIN TISSUE SAF's. ...TSS


TSE & HOUNDS

GAH WELLS (very important statement here...TSS)

HOUND STUDY

AS implied in the Inset 25 we must not _ASSUME_ that transmission of BSE to other species will invariably present pathology typical of a scrapie-like disease.

snip...


76 pages on hound study;

snip...


39.Hound ataxia had reportedly been occurring since the 1930's, and a known risk factor for its development was the feeding to hounds of downer cows, and particularly bovine offal. Circumstantial evidence suggests that bovine offal may also be causal in FSE, and TME in mink. Despite the inconclusive nature of the neuropathology, it was clearly evident that this putative canine spongiform encephalopathy merited further investigation.

40.The inconclusive results in hounds were never confirmed, nor was the link with hound ataxia pursued. I telephoned Robert Higgins six years after he first sent the slides to CVL. I was informed that despite his submitting a yearly report to the CVO including the suggestion that the hound work be continued, no further work had been done since 1991. This was surprising, to say the very least.

41.The hound work could have provided valuable evidence that a scrapie-like agent may have been present in cattle offal long before the BSE epidemic was recognised. The MAFF hound survey remains unpublished.

Histopathological support to various other published MAFF experiments

42.These included neuropathological examination of material from experiments studying the attempted transmission of BSE to chickens and pigs (CVL 1991) and to mice (RVC 1994). http://www.bseinquiry.gov.uk/witness/htm/stat067.htm


Monday, February 14, 2011

THE ROLE OF PREDATION IN DISEASE CONTROL: A COMPARISON OF SELECTIVE AND NONSELECTIVE REMOVAL ON PRION DISEASE DYNAMICS IN DEER

NO, NO, NOT NO, BUT HELL NO !

Journal of Wildlife Diseases, 47(1), 2011, pp. 78-93 © Wildlife Disease Association 2011


Monday, March 8, 2010

Canine Spongiform Encephalopathy aka MAD DOG DISEASE


=============================

FRIDAY, DECEMBER 14, 2012 

Susceptibility of domestic cats to chronic wasting disease

Candace K. Mathiason1,#, Amy V. Nalls1, Davis M. Seelig1, Susan L. Kraft2, Kevin Carnes2, Kelly R. Anderson1, Jeanette Hayes-Klug1 and Edward A. Hoover1

+ Author Affiliations

1Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523 2Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523

ABSTRACT

Domestic and non-domestic cats have been shown to be susceptible to feline spongiform encephalopathy (FSE), almost certainly caused by consumption of bovine spongiform encephalopathy (BSE)-contaminated meat. Because domestic and free-ranging non-domestic felids scavenge cervid carcasses, including those in areas affected by chronic wasting disease (CWD), we evaluated the susceptibility of the domestic cat (Felis catus) to CWD infection experimentally. Cohorts of n=5 cats each were inoculated intracerebrally (IC) or orally (PO) with CWD-infected deer brain. At 40 and 42 months post inoculation, two IC-inoculated cats developed signs consistent with prion disease including a stilted gait, weight loss, anorexia, polydipsia, patterned motor behaviors, head and tail tremors and ataxia, and progressed to terminal disease within 5 months. Brains from these two cats were pooled and inoculated into cohorts of cats by IC, PO, and IP/SQ (intraperitoneal/subcutaneous) routes. Upon sub-passage, feline CWD was transmitted to all IC-inoculated cats with a decreased incubation period of 23-27 months. Feline-adapted CWD (FelCWD) was demonstrated in the brains of all the affected cats by western blot and immunohistochemical analysis. Magnetic resonance imaging revealed abnormalities in clinically ill cats, which included multifocal T2 FLAIR signal hyperintensities, ventricular size increases, prominent sulci and white matter tract cavitation. Currently, 3 of 4 IP/SQ and 2 of 4 PO secondary passage inoculated cats have developed abnormal behavior patterns consistent with the early stage of feline CWD. These results demonstrate that CWD can be transmitted and adapted to the domestic cat, thus raising the issue of potential cervid-to-feline transmission in nature.

FOOTNOTES

↵# To whom correspondence should be addressed. candace.mathiason@colostate.edu, 1619 Campus Delivery, Fort Collins, CO 80523-1619, 970 491-3975

Copyright © 2012, American Society for Microbiology. All Rights Reserved.


HOWEVER, why ignore the old science and transmission studies to date ???

Species Born Onset/Died

Ocelot May 1987 Mar 1994 Ocelot Jul 1980 Oct 1995 Puma 1986 May 1991 Puma 1980 May 1995 Puma 1978 May 1995 Lion Nov 1986 Dec 1998 Tiger 1981 Dec 1995 Tiger Feb 1983 Oct 1998 Ankole 1987 May 1995 Ankole 1986 Feb 1991 Bison 1989/90 Oct 1996

Maff data on 15 May 99

kudu 6 gemsbok 1 nyala 1 oryx 2 eland 6 cheetah 9 puma 3 tiger 2 ocelot 2 bison 1 ankole 2 lion 1


Feline Spongiform Encephalopathy (FSE) FSE was first identified in the UK in 1990. Most cases have been reported in the UK, where the epidemic has been consistent with that of the BSE epidemic. Some other countries (e.g. Norway, Liechtenstein and France) have also reported cases.

Most cases have been reported in domestic cats but there have also been cases in captive exotic cats (e.g. Cheetah, Lion, Asian leopard cat, Ocelot, Puma and Tiger). The disease is characterised by progressive nervous signs, including ataxia, hyper-reactivity and behavioural changes and is fatal.

The chemical and biological properties of the infectious agent are identical to those of the BSE and vCJD agents. These findings support the hypothesis that the FSE epidemic resulted from the consumption of food contaminated with the BSE agent.

The FSE epidemic has declined as a result of tight controls on the disposal of specified risk material and other animal by-products.

References: Leggett, M.M. et al.(1990) A spongiform encephalopathy in a cat. Veterinary Record. 127. 586-588

Synge, B.A. et al. (1991) Spongiform encephalopathy in a Scottish cat. Veterinary Record. 129. 320

Wyatt, J. M. et al. (1991) Naturally occurring scrapie-like spongiform encephalopathy in five domestic cats. Veterinary Record. 129. 233.

Gruffydd-Jones, T. J.et al.. (1991) Feline spongiform encephalopathy. J. Small Animal Practice. 33. 471-476.

Pearson, G. R. et al. (1992) Feline spongiform encephalopathy: fibril and PrP studies. Veterinary Record. 131. 307-310.

Willoughby, K. et al. (1992) Spongiform encephalopathy in a captive puma (Felis concolor). Veterinary Record. 131. 431-434.

Fraser, H. et al. (1994) Transmission of feline spongiform encephalopathy to mice. Veterinary Record 134. 449.

Bratberg, B. et al. (1995) Feline spongiform encephalopathy in a cat in Norway. Veterinary Record 136. 444

Baron, T. et al. (1997) Spongiform encephalopathy in an imported cheetah in France. Veterinary Record 141. 270-271

Zanusso, G et al. (1998) Simultaneous occurrence of spongiform encephalopathy in a man and his cat in Italy. Lancet, V352, N9134, OCT 3, Pp 1116-1117.

Ryder, S.J. et al. (2001) Inconsistent detection of PrP in extraneural tissues of cats with feline spongiform encephalopathy. Veterinary Record 146. 437-441

Kelly, D.F. et al. (2005) Neuropathological findings in cats with clinically suspect but histologically unconfirmed feline spongiform encephalopathy. Veterinary Record 156. 472-477.

TSEs in Exotic Ruminants TSEs have been detected in exotic ruminants in UK zoos since 1986. These include antelopes (Eland, Gemsbok, Arabian and Scimitar oryx, Nyala and Kudu), Ankole cattle and Bison. With hindsight the 1986 case in a Nyala was diagnosed before the first case of BSE was identified. The TSE cases in exotic ruminants had a younger onset age and a shorter clinical duration compared to that in cattle with BSE. All the cases appear to be linked to the BSE epidemic via the consumption of feed contaminated with the BSE agent. The epidemic has declined as a result of tight controls on feeding mammalian meat and bone meal to susceptible animals, particularly from August 1996.

References: Jeffrey, M. and Wells, G.A.H, (1988) Spongiform encephalopathy in a nyala (Tragelaphus angasi). Vet.Path. 25. 398-399

Kirkwood, J.K. et al (1990) Spongiform encephalopathy in an Arabian oryx (Oryx leucoryx) and a Greater kudu (Tragelaphus strepsiceros) Veterinary Record 127. 418-429.

Kirkwood, J.K. (1993) Spongiform encephalopathy in a herd of Greater kudu (Tragelaphus strepsiceros): epidemiological observations. Veterinary Record 133. 360-364

Kirkwood, J. K. and Cunningham, A.A. (1994) Epidemiological observations on spongiform encephalopathies in captive wild animals in the British Isles. Veterinary Record. 135. 296-303.

Food and Agriculture Organisation (1998) Manual on Bovine Spongiform Encephalopathy.


TSE and Surveillance Statistics Exotic species and domestic cats November 2018 

Contents Number of confirmed cases of FSE in domestic cats by year 

Number of confirmed cases of FSE in domestic cats by year of birth 

Number of TSEs in exotic species by year reported

Transmissible Spongiform Encephalopathies in exotic species

Number of confirmed cases of FSE in domestic cats by year Data valid to 30 November 2018 Includes one case from Guernsey Year Reported No. of cases 1988 0 1989 0 1990 12 1991 12 1992 10 1993 11 1994 16 1995 8 1996 6 1997 6 1998 4 1999 2 2000 1 2001 1 2002 0 2003 0 2004 0 2005 0 2006 0 2007 0 2008 0 2009 0 2010 0 2011 0 2012 0 2013 0 2014 0 2015 0 2016 0 2017 0 2018 0 Total 89 Year of Onset No. of cases 1988 0 1989 1 1990 16 1991 11 1992 14 1993 10 1994 14 1995 4 1996 7 1997 8 1998 1 1999 1 2000 1 2001 1 2002 0 2003 0 2004 0 2005 0 2006 0 2007 0 2008 0 2009 0 2010 0 2011 0 2012 0 2013 0 2014 0 2015 0 2016 0 2017 0 2018 0 Total 89


FSE: FIRST CONFIRMED CASE REPORTED IN PORTUGAL AND POTENTIAL MAD CAT ESCAPES LAB IN USA Date: August 9, 2007 at 2:27 pm PST

DIA-45 FELINE SPONGIFORM ENCEPHALOPATHY: FIRST CONFIRMED CASE REPORTED IN PORTUGAL

J.F. Silva1, J.J. Correia, 1 J. Ribeiro2, S. Carmo2 and L.Orge3

1 Faculdade de Medicina Veterinária (UTL), Lisbon, Portugal 2 Clínica Veterinária Ani+, Queluz, Portugal 3 Laboratório Nacional de Investigação Veterinária, Unidade de BSE, Lisbon, Portugal

Feline spongiform encephalopathy (FSE), affecting domestic and captive feline species, is a prion disease considered to be related to bovine spongiform encephalopathy (BSE). Here we report the first case diagnosed in Portugal, highlighting the neuroapthological findings. In 2004 a 9-year old intact female Siamese cat was referred with chronic progressive behavioural changes, polydipsia, gait abnormalities and episodes of hypersalivation. Clinical signs progressed to tetraparesis and dementia and euthanasia was performed. At necropsy, brain and spinal cord had no significative changes. Tissue samples from brain, cerebellum, brainstem and spinal cord were collected for histopathology and immunohistochemistry for detection of PrPres. Histology revealed neuropil and neuronal perikarion vacuolation in several areas of the central nervous system together with gliosis and cell rarefaction at the granular layer of the cerebellum. Immunohistochemical detection of PrPres showed a strong and widespread PrPres accumulation as granular and linear deposits as well as associated with some neurons. These findings are supportive of FSE. To the authors knowledge this is the first confirmed case of FSE reported in Portugal.




DOCKET-- 03D-0186 -- FDA Issues Draft Guidance on Use of Material From Deer and Elk in Animal Feed; Availability

Date: Fri, 16 May 2003 11:47:37 –0500

EMC 1 Terry S. Singeltary Sr. Vol #: 1


IN CONFIDENCE CJD TO CATS...

It should be noted that under experimental conditions cats succumb to an encephalopathy after intracerebral inoculation of material derived from patients affected with Creutzfeldt-Jakob Disease.


FELINE SPONGIFORM ENCEPHALOPATHY FSE



Monday, November 14, 2022 

Prion Diseases in Dromedary Camels (CPD) 2022 Review 


MONDAY, OCTOBER 10, 2022

Docket No: 2002N-0273 (formerly Docket No. 02N-0273) Substances Prohibited From Use in Animal Food and Feed Scientists Comments December 20, 2005


TUESDAY, SEPTEMBER 07, 2021

Atypical Bovine Spongiform Encephalopathy BSE OIE, FDA 589.2001 FEED REGULATIONS, and Ingestion Therefrom


SUNDAY, OCTOBER 30, 2022 
Why is USDA "only" testing 25,000 samples a year?

https://bovineprp.blogspot.com/2022/10/why-is-usda-only-testing-25000-samples.html
SUNDAY, OCTOBER 16, 2022 

USDA Transmissible Spongiform Encephalopathy TSE Prion Action Plan National Program 103 Animal Health 2022-2027 



IMO, basing regulations of TSE Prion disease on a whelm, supposition, hope, that canine are totally resistant of any TSE Prion disease, IMO, is foolish...

Terry S. Singeltary Sr. 
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