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Potentiating tangle formation reduces acute toxicity of soluble tau species in the rat

Abstract : Tauopathies are neurodegenerative diseases characterized by the aggregation of tau protein. These pathologies exhibit a wide variety of clinical and anatomo-pathological presentations, which may result from different pathological mechanisms. Although tau inclusions are a common feature in all these diseases, recent evidence instead implicates small oligomeric aggregates as drivers of tau-induced toxicity. Hence $in\ vivo$ model systems displaying either soluble or fibrillary forms of wild-type or mutant tau are needed to better identify their respective pathological pathways. Here we used adeno-associated viruses to mediate gene transfer of human tau to the rat brain to develop models of pure tauopathies. Two different constructs were used, each giving rise to a specific phenotype developing in less than 3 months. First, hTAU$^{WT}$ overexpression led to a strong hyperphosphorylation of the protein, which was associated with neurotoxicity in the absence of any significant aggregation. In sharp contrast, its co-expression with the pro-aggregation peptide TauRD-$\Delta$K280 in the hTAU$^{ProAggr}$group strongly promoted its aggregation into Gallyas-positive neurofibrillary tangles, while preserving neuronal survival. Our results support the hypothesis that soluble tau species are key players of tau-induced neurodegeneration.
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Marie D’orange, Gwenaëlle Auregan, Dimitri Cheramy, Mylène Gaudin-Guérif, Sarah Lieger, et al.. Potentiating tangle formation reduces acute toxicity of soluble tau species in the rat. Brain - A Journal of Neurology , Oxford University Press (OUP), 2018, 141 (2), pp.535-549. ⟨10.1093/brain/awx342⟩. ⟨cea-02074052⟩



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