Abstract:Tauopathies are a family of neurodegenerative diseases in which fibrils of human hyperphosphorylated tau (P-tau) are believed to cause neuropathology. In Alzheimer disease, P-tau associates with A-beta amyloid and contributes to disease pathogenesis. In familial human prion diseases and variant CJD, P-tau often co-associates with prion protein amyloid, and might also accelerate disease progression. To test this latter possibility, here we compared progression of amyloid prion disease in vivo after scrapie infe… Show more
“…6c, d). Thus, despite the co-localization of p.tau with PrP TSE amyloid plaques in 87V-VM scrapie, and association with plaques described in other studies [19], [49], [50] results obtained in GSS-22 mice (overexpressor) and 101LL mice inoculated with recombinant PrP fibrils show that PrP-amyloidogenesis is not invariably associated with the formation of p.tau isoforms (Table 3). Fig.…”
Section: Resultsmentioning
confidence: 61%
“…In Gerstmann-Strӓussler-Scheinker disease (GSS), variant Creutzfeldt-Jakob disease (vCJD) and some forms of sporadic CJD (sCJD), p.tau is mostly seen in the vicinity of amyloid plaques [17]. P.tau deposition has also been observed in mouse models of prion disease [18], [19], [20]. Despite these observations, analysis of knock-out [21] and overexpression [22] tau mouse models suggests that tau is not essential for the development of prion disease.…”
The conversion of cellular prion protein (PrP) into a misfolded isoform is central to the development of prion diseases. However, the heterogeneous phenotypes observed in prion disease may be linked with the presence of other misfolded proteins in the brain. While hyperphosphorylated tau (p.tau) is characteristic of Alzheimer's disease (AD), p.tau is also observed in human prion diseases. To explore this association in the absence of potential effects due to aging, drug treatment, agonal stage and postmortem delay we analyzed p.tau and PrP immunopositivity in mouse models. Analyses were performed on mice inoculated with prion agents, and mice with PrP amyloid in the absence of prion disease. We observed that p.tau was consistently present in animals with prion infectivity (models that transmit disease upon serial passage). In contrast, p.tau was very rarely observed or absent in mice with PrP amyloid plaques in the absence of prion replication. These data indicate that the formation of p.tau is not linked to deposition of misfolded PrP, but suggest that the interaction between replication of infectivity and host factors regulate the formation of p.tau and may contribute to the heterogeneous phenotype of prion diseases.
“…6c, d). Thus, despite the co-localization of p.tau with PrP TSE amyloid plaques in 87V-VM scrapie, and association with plaques described in other studies [19], [49], [50] results obtained in GSS-22 mice (overexpressor) and 101LL mice inoculated with recombinant PrP fibrils show that PrP-amyloidogenesis is not invariably associated with the formation of p.tau isoforms (Table 3). Fig.…”
Section: Resultsmentioning
confidence: 61%
“…In Gerstmann-Strӓussler-Scheinker disease (GSS), variant Creutzfeldt-Jakob disease (vCJD) and some forms of sporadic CJD (sCJD), p.tau is mostly seen in the vicinity of amyloid plaques [17]. P.tau deposition has also been observed in mouse models of prion disease [18], [19], [20]. Despite these observations, analysis of knock-out [21] and overexpression [22] tau mouse models suggests that tau is not essential for the development of prion disease.…”
The conversion of cellular prion protein (PrP) into a misfolded isoform is central to the development of prion diseases. However, the heterogeneous phenotypes observed in prion disease may be linked with the presence of other misfolded proteins in the brain. While hyperphosphorylated tau (p.tau) is characteristic of Alzheimer's disease (AD), p.tau is also observed in human prion diseases. To explore this association in the absence of potential effects due to aging, drug treatment, agonal stage and postmortem delay we analyzed p.tau and PrP immunopositivity in mouse models. Analyses were performed on mice inoculated with prion agents, and mice with PrP amyloid in the absence of prion disease. We observed that p.tau was consistently present in animals with prion infectivity (models that transmit disease upon serial passage). In contrast, p.tau was very rarely observed or absent in mice with PrP amyloid plaques in the absence of prion replication. These data indicate that the formation of p.tau is not linked to deposition of misfolded PrP, but suggest that the interaction between replication of infectivity and host factors regulate the formation of p.tau and may contribute to the heterogeneous phenotype of prion diseases.
“…This hypothesis has been supported by genetic forms of AD due to mutations in the AβPP , PSEN1 , and PSEN2 genes that consistently alter the metabolism of Aβ, with a consequent Tau hyperphosphorylation and formation of Tau aggregates in vitro and in vivo [ 15 , 19 , 28 ]. Altered Tau metabolism in association with APrP has also been observed in in vitro studies [ 42 ] and in vivo in mouse models [ 48 , 50 ]. By determining the structure of the core of Tau filaments from diseases caused by two distinct PRNP mutations, F198S and Q160X, to be identical to the core of Tau filaments from AD, we uncover potential links between amyloid proteins and the resulting Tau aggregation.…”
In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) with a nonsense mutation in the PRNP gene that leads to early termination of translation of PrP (Q160Ter or Q160X), and Gerstmann–Sträussler–Scheinker (GSS) disease, with a missense mutation in the PRNP gene that leads to an amino acid substitution at residue 198 (F198S) of PrP. The clinical and neuropathologic phenotypes associated with these two mutations in PRNP are different; however, the neuropathologic analyses of these two genetic variants have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA (Q160X) and GSS (F198S) are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA (Q160X), Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS (F198S), only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA (Q160X) and GSS (F198S) brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA (Q160X) and GSS (F198S) are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of extracellular amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.
“…In the P105L variant of GSS, dystrophic, tau-positive neurites and neurofibrillary tangles were observed in PrP Sc plaques, even in the absence of senile Aβ amyloid plaques [ 30 ]. Associations between PrP Sc plaques and tau aggregation were observed in scrapie-infected mouse brains of human tau transgenic mice [ 31 ]. Thus, direct pathological interactions between PrP Sc and tau in the absence of Aβ facilitating the progression of the disease could be a plausible hypothesis for AD and sCJD comorbidity.…”
Alzheimer’s disease (AD) and sporadic Creutzfeldt–Jakob disease (sCJD) are both characterized by extracellular pathologically conformed aggregates of amyloid proteins—amyloid β-protein (Aβ) and prion protein (PrPSc), respectively. To investigate the potential morphological colocalization of Aβ and PrPSc aggregates, we examined the hippocampal regions (archicortex and neocortex) of 20 subjects with confirmed comorbid AD and sCJD using neurohistopathological analyses, immunohistochemical methods, and confocal fluorescent microscopy. Our data showed that extracellular Aβ and PrPSc aggregates tended to be, in most cases, located separately, and “compound” plaques were relatively rare. We observed PrPSc plaque-like structures in the periphery of the non-compact parts of Aβ plaques, as well as in tau protein-positive dystrophic structures. The AD ABC score according to the NIA-Alzheimer’s association guidelines, and prion protein subtype with codon 129 methionine–valine (M/V) polymorphisms in sCJD, while representing key characteristics of these diseases, did not correlate with the morphology of the Aβ/PrPSc co-aggregates. However, our data showed that PrPSc aggregation could dominate during co-aggregation with non-compact Aβ in the periphery of Aβ plaques.
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