Hyperphosphorylated tau deposition parallels prion protein burden in a case of Gerstmann-Sträussler-Scheinker syndrome P102L mutation complicated with dementia

Ishizawa, Keisuke; Komori, Takashi; Shimazu, Tomokazu; Yamamoto, Toshiyuki; Kitamoto, Tetsuyuki; Shiota, Kunio; Hirose, Takanori

doi:10.1007/s00401-002-0547-3

Cited by 44 publications

(35 citation statements)

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“…p-Tau has been reported in brains of patients with Gerstmann-Sträussler-Scheinker (GSS) disease associated with one of a number of mutations in the PRNP gene: P105L, G131N, S132I, H187R, F198S, D202N, Q217R, Y218N and Q227X (Nochlin et al, 1989; Kitamoto et al, 1993; Tagliavini et al, 1993; Ghetti et al, 1996; Piccardo et al, 1998; Malucci et al, 1999; Panegyres et al, 2001; Ishizawa et al, 2002; Colucci et al, 2006; Alzualde et al, 2010; Jansen et al 2010; Ghetti et al, 2011; Reiniger et al, 2011). p-Tau has also been described in brains of patients with Prion Protein Cerebral Amyloid Angiopathy associated with PRNP point mutations Y145X, Y160X and Y163X (Ghetti et al, 1996b; Holton et al, 2010; Jayadev et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Both diseases are characterized by the presence of PrP amyloid; some patients with GSS disease show co-deposition of PrP with Aβ-amyloid (Ghetti et al, 1996a). Such findings suggest that tau pathology is more likely to be a secondary “downstream” pathogenic process resulting from the primary illness rather than causing extracellular amyloid to accumulate (Ghetti et al, 1996; Ishizawa et al, 2002). Tau pathology has also been described in brains of vCJD patients, experimental vCJD in mice and experimental BSE in transgenic mice expressing bovine PrP (Bautista et al, 2006; Giaccone et al, 2008; Sikorska et al, 2009; Reiniger et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

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Squirrel Monkeys (Saimiri sciureus) Infected with the Agent of Bovine Spongiform Encephalopathy Develop Tau Pathology

Piccardo

Cervenak

Yakovleva

et al. 2012

Journal of Comparative Pathology

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Squirrel monkeys were experimentally infected with the classical bovine spongiform encephalopathy (BSE) agent. Two to four years later, six of the monkeys developed alterations in interactive behavior, cognition and other neurological signs typical of transmissible spongiform encephalopathy (TSE). At necropsy, all brains showed pathological changes similar to those described in variant Creutzfeldt-Jakob disease (vCJD) of humans, except that the squirrel monkey brains contained no PrP amyloid plaques typical of that disease. Constant neuropathological features included spongiform degeneration, gliosis, deposition of abnormal prion protein (PrPTSE) and many deposits of abnormally phosphorylated tau protein (p-Tau) in several areas of the cerebrum and cerebellum. Western blots showed large amounts of proteinase-K-resistant prion protein in the central nervous system. The striking absence of PrP plaques (prominent in brains of cynomolgus macaques with both experimental BSE and vCJD and in patients with vCJD) reinforces the conclusion that the host plays a major role in determining the neuropathology of TSEs. Results of this study suggest that p-Tau, found in the brains of all BSE-infected monkeys, might play a role in the pathogenesis of TSEs. Whether p-Tau contributes to development of disease or appears as a secondary change late in the course of illness remains to be determined.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Squirrel Monkeys (Saimiri sciureus) Infected with the Agent of Bovine Spongiform Encephalopathy Develop Tau Pathology

Piccardo

Cervenak

Yakovleva

et al. 2012

Journal of Comparative Pathology

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“…The amyloid cascade hypothesis implies that the extracellular deposition of Aβ is the initial and seminal event of AD pathogenesis and the intraneuronal formation of neurofibrillary changes, composed of hyperphosphorylated tau protein, is a consequence of it. In prion disease, a consistent subset of GSS patients, such as some with the most common P102L PRNP mutation, has been shown to harbor neurofibrillary changes further suggesting that tau pathology is downstream from the extracellular deposition of amyloid, either made up of Aβ or PrP [30]. But this has been partially questioned by the fact that in most cases of human prion diseases, the deposition of abnormal PrP in the brain does not induce a tauopathy.…”

Section: Discussionmentioning

confidence: 99%

Changes of tau profiles in brains of the hamsters infected with scrapie strains 263 K or 139 A possibly associated with the alteration of phosphate kinases

et al. 2010

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BackgroundPhospho-tau deposition has been described in a rare genetic human prion disease, Gerstmann-Sträussler-Scheinker syndrome, but is not common neuropathological picture for other human and animal transmissible spongiform encephalopathies (TSEs). This study investigated the possible changes of tau and phosphorylated tau (p-tau, at Ser396, Ser404, and Ser202/Thr205) in scrapie experimental animals.MethodsThe profiles of tau and p-tau (p-tau, at Ser396, Ser404, and Ser202/Thr205) in the brain tissues of agents 263K- or 139A-infected hamsters were evaluated by Western blots and real-time PCR. Meanwhile, the transcriptional and expressive levels of GSK3β and CDK5 in the brains were tested.ResultsThe contents of total tau and p-tau at Ser202/Thr205 increased, but p-tau at Ser396 and Ser404 decreased at the terminal stages, regardless of scrapie strains. Transcriptional levels of two tau isoforms were also increased. Additionally, it showed higher CDK5, but lower GSK3β transcriptional and expressive levels in the brains of scrapie-infected animals. Analysis of brain samples collected from different times after inoculated with agent 263 K revealed that the changes of tau profiles and phosphate kinases were time-relative events.ConclusionThese data suggest that changes of profiles of p-tau at Ser396, Ser404 and Ser202/Thr205 are illness-correlative phenomena in TSEs, which may arise of the alteration of phosphate kinases. Alteration of tau, p-tau (Ser396, Ser404, and Ser202/Thr205), GSK3β and CDK5 were either intermediate or consequent events in TSE pathogenesis and proposed the potential linkage of these bioactive proteins with the pathogenesis of prion diseases.

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“…The absence of Aβ deposits in the frontal cortex of case #14 indicates that the severe tau pathology is related to the unusual PrP pathology rather than to concomitant AD pathology. Neurofibrillary tau pathology has been documented earlier in other rare hereditary prion disease cases in which mutations in PRNP cause truncation of PrP and absence of the GPI anchor [51, 52] as well as other forms of GSS caused by distinct PRNP mutations [53–55]. Notably, the presence of GVD was previously mentioned by a case report on a longstanding GSS patient (P102L) with pathological features comparable to case #14, showing neurofibrillary tau pathology secondarily induced by prion amyloidosis [53].…”

Section: Discussionmentioning

confidence: 99%

“…Neurofibrillary tau pathology has been documented earlier in other rare hereditary prion disease cases in which mutations in PRNP cause truncation of PrP and absence of the GPI anchor [51, 52] as well as other forms of GSS caused by distinct PRNP mutations [53–55]. Notably, the presence of GVD was previously mentioned by a case report on a longstanding GSS patient (P102L) with pathological features comparable to case #14, showing neurofibrillary tau pathology secondarily induced by prion amyloidosis [53]. Molecular properties of the prion protein itself as well as the duration of the clinical course could be requisites for the emergence of neurofibrillary tau pathology and UPR activation in human prion diseases.…”

Section: Discussionmentioning

confidence: 99%

Activation of the unfolded protein response and granulovacuolar degeneration are not common features of human prion pathology

Wiersma

Hecke

Scheper

et al. 2016

acta neuropathol commun

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Human prion diseases are fatal neurodegenerative disorders with a genetic, sporadic or infectiously acquired aetiology. Neuropathologically, human prion diseases are characterized by deposition of misfolded prion protein and neuronal loss. In post-mortem brain tissue from patients with other neurodegenerative diseases characterized by protein misfolding, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration with tau pathology (FTLD-tau), increased activation of the unfolded protein response (UPR) has been observed. The UPR is a cellular stress response that copes with the presence of misfolded proteins. Recent studies have indicated that UPR activation is also involved in experimental models of prion disease and have suggested intervention in the UPR as a therapeutic strategy. On the other hand, it was previously shown that the active form of the UPR stress sensor dsRNA-activated protein kinase-like ER kinase (PERK) is not increased in post-mortem brain tissue samples from human prion disease cases. In the present study, we assessed the active form of another UPR stress sensor, inositol-requiring enzyme 1α (IRE1α), in human post-mortem frontal cortex of a large cohort of sporadic, inherited and acquired prion disease patients (n = 47) and non-neurological controls. Immunoreactivity for phosphorylated IRE1α was not increased in prion disease cases compared with non-neurological controls. In addition, immunoreactivity for phosphorylated PERK was unaltered in human prion disease cases included in the current cohort. Moreover, no difference in the extent of granulovacuolar degeneration, a pathological feature associated with the presence of UPR activation markers, was detected. Our data indicate that, in contrast to AD and primary tauopathies, activation of the UPR is not a common feature of human prion pathology.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0383-7) contains supplementary material, which is available to authorized users.

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Hyperphosphorylated tau deposition parallels prion protein burden in a case of Gerstmann-Sträussler-Scheinker syndrome P102L mutation complicated with dementia

Cited by 44 publications

References 38 publications

Squirrel Monkeys (Saimiri sciureus) Infected with the Agent of Bovine Spongiform Encephalopathy Develop Tau Pathology

Squirrel Monkeys (Saimiri sciureus) Infected with the Agent of Bovine Spongiform Encephalopathy Develop Tau Pathology

Changes of tau profiles in brains of the hamsters infected with scrapie strains 263 K or 139 A possibly associated with the alteration of phosphate kinases

Activation of the unfolded protein response and granulovacuolar degeneration are not common features of human prion pathology

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