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O1–07–05: In vivo tau spreading relies on the transsynaptic transfer of soluble wild‐type tau species
Author(s) -
Buee Luc,
Dujardin Simon,
Bégard Séverine,
Raphaëlle Caillierez,
Lécolle Katia,
Dufour Noelle,
Auregan Gwenaelle,
Winderickx Joris,
Philippe Hantraye,
Deglon Nicole,
Colin Morvane
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.04.090
Subject(s) - olfactory bulb , progressive supranuclear palsy , tau protein , hippocampus , neuroscience , in vivo , tau pathology , immunohistochemistry , chemistry , biology , microbiology and biotechnology , pathology , alzheimer's disease , medicine , central nervous system , disease
Background: Aberrant intracellular inclusions composed of hyperphosphorylated filamentous tau are a neuropathological hallmark of Alzheimer’s disease, progressive supranuclear palsy and other sporadic neurodegenerative disorders, which have been collectively termed tauopathies. The discovery that pathogenic mutations in the tau gene (MAPT) can cause a familial neurodegenerative tauopathy has provided compelling evidence that tau dysfunction is sufficient to cause neurodegeneration. Therefore inhibiting potentially toxic events such as tau inclusion formation are attractive targets for therapeutic intervention and disease prevention. A string of recent in vitro and in vivo studies have shown that tau aggregates have ’prion-like’ properties which not only allow them to transmit/seed further tau aggregation, but also spread to neighbouring cells or connected brain regions. This process is referred to as ’tau propagation’ and might explain the stereotypic progression of tau pathology in Alzheimer’s disease and other tauopathies. Methods: In this study, we report a novel in vivo model of tau propagation using young asymptomatic P301S transgenic mice that underwent unilateral hippocampal infusions containing brain extracts from older clinically impaired P301S mice, known to have florid tau aggregates. Detailed neuropathological examination was conducted in these mice (and controls) at various time-points post-infusion to investigate the presence and distribution of tau pathology. Results: Infusion-related tau pathology was induced rapidly (within 2 weeks) in the hippocampus of this model. Tau-positive neurofibrillary tangles increased in a stereotypic and progressive fashion, with robust Gallyas-positive tangles being observed 1 month post-infusion. Contralateral and anterior/posterior spread of tau pathologywas also evident and appeared to be dependent on synaptic connectivity rather than spatial proximity. Tau biochemistry confirmed the induction and spread of tau pathology in this model.Conclusions: Previously reportedmodels of tau propagation take several months to develop significant tau pathology attributable to propagation, therefore the rapid and robust propagation phenotype in our model will be instrumental to both basic research and the drug discovery process, with the ultimate aim to find intervention and prevention strategies for human tauopathies.