Potentiating tangle formation reduces acute toxicity of soluble tau species in the rat
Potentiating tangle formation reduces acute toxicity of soluble tau species in the rat
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DOI：
10.1093/brain/awx342
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发表时间：
2018-02-01
期刊：
影响因子：
14.5
通讯作者：
Cambon, Karine
中科院分区：
文献类型：
--
作者：
d'Orange, Marie;Auregan, Gwenaelle;Cambon, Karine
Tau病是以tau蛋白聚集为特征的神经退行性疾病。这些病理表现出各种各样的临床和解剖病理表现，这可能是不同的病理机制所致。虽然tau包涵体是所有这些疾病的共同特征，但最近的证据表明，小的寡聚体是tau诱导的毒性的驱动因素。因此，需要显示野生型或突变型tau的可溶型或纤维型的体内模型系统，以更好地识别它们各自的病理途径。在这里，我们使用腺相关病毒介导人tau基因转移到大鼠脑内，以建立单纯tau病的模型。使用了两种不同的结构，每种结构都在不到3个月的时间内产生了一种特定的表型。首先，hTAU(WT)的过度表达导致蛋白质的强烈过度磷酸化，在没有任何显著聚集的情况下，这与神经毒性有关。与之形成鲜明对比的是，在hTAU(ProAggr)组中，它与支持聚集的多肽TauRD-Delta K280的共表达强烈地促进了其聚集成Galyas阳性的神经原纤维缠结，同时保持了神经元的存活。我们的结果支持这一假说，即可溶性tau物种是tau诱导的神经变性的关键角色。
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.