Acta Neuropathologica: 光动力研究显示tau包裹体的快速形成和明显转化

2021-02-17 MedSci原创 MedSci原创

包括阿尔茨海默病(AD)在内的神经退行性疾病与脑内异常聚集的tau蛋白的细胞内积聚密切相关。

包括阿尔茨海默病(AD)在内的神经退行性疾病与脑内异常聚集的tau蛋白的细胞内积聚密切相关。未结合的微管相关蛋白tau(MAPT)在生理上以可溶性非结构蛋白的形式存在,但在致病条件下,tau在AD和其它tau病中聚集成不溶的富含β-折叠的淀粉样原纤维包裹体。值得注意的是,这些包裹体被广泛的翻译后修饰,其具有显著的过度磷酸化。

在AD中,tau在神经原纤维缠结(NFTs)中的积累与认知功能减退、脑萎缩和神经元丢失显著相关。相反,人们也认识到tau包裹体在人类神经元中可能保持稳定数十年。最近的证据表明,在具有NFT病理学的tau转基因小鼠中,其神经元功能并未受损。尽管我们对tau累积和tau相关神经退行性病变的机制知之甚少,但遗传学、模型和病理学研究都支持tau在神经退行性疾病中的治疗靶向性,但关于tau包裹体形成和清除动力学的信息仍有限。

本研究利用rAAV载体介导Dendra2标记的人野生型、P301L和前聚集的P301L/S320F tau蛋白的表达,在添加和不添加外源性tau原纤维种子的情况下,研究人员使用长期光脉冲标记方法评估了器官型脑片培养(BSC)模型中tau包裹体的动力学。

研究表明,tau包裹体通常在tau病BSC模型中12-96h形成。出乎意料的是,包裹体中的tau有明显的周转,当包裹体新形成时,其平均半衰期约为1周。当含包裹体的BSC在培养中长时间老化时,tau包裹体继续周转,但在培养1个月和2个月后,其半衰期分别增加到~2周和~3周。单个tau包裹体可以是长寿命的,其可能在这些BSC模型中持续数月,甚至在人脑中持续更长时间。然而,本文的数据表明,tau包裹体不是静止的,而是具有可感知周转的动态结构。

综上所述,了解介导这种包裹体转变的细胞过程可能会产生新的治疗策略,从而可能逆转病理性tau包裹体的形成。

Croft, C.L., Goodwin, M.S., Ryu, D.H. et al. Photodynamic studies reveal rapid formation and appreciable turnover of tau inclusions. Acta Neuropathol 141, 359–381 (2021). https://doi.org/10.1007/s00401-021-02264-9

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    2021-11-07 windight
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    2021-11-06 yb6560
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    2021-02-19 hb2008ye
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