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Orange, Marie d'; Auregan, Gwenaelle; Cheramy, Dimitri; Gaudin-Guerif, Mylene; Lieger, Sarah; Guillermier, Martine; Stimmer, Lev; Josephine, Charlene; Herard, Anne-Sophie; Gaillard, Marie-Claude; Petit, Fanny; Kiessling, Maren Christine; Schmitz, Christoph; Colin, Morvane; Buee, Luc; Panayi, Fany; Diguet, Elsa; Brouillet, Emmanuel; Hantraye, Philippe; Bemelmans, Alexis-Pierre; Cambon, Karine (2018): Potentiating tangle formation reduces acute toxicity of soluble tau species in the rat. In: Brain, Vol. 141: pp. 535-549
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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.