Department of Brain and Neurosciences, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
Brain. 2021 Sep 4;144(8):2333-2348. doi: 10.1093/brain/awab091.
Tauopathies are a subset of neurodegenerative diseases characterized by abnormal tau inclusions. Specifically, three-repeat tau and four-repeat tau in Alzheimer's disease, three-repeat tau in Pick's disease (PiD) and four-repeat tau in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) form amyloid-like fibrous structures that accumulate in neurons and/or glial cells. Amplification and cell-to-cell transmission of abnormal tau based on the prion hypothesis are believed to explain the onset and progression of tauopathies. Recent studies support not only the self-propagation of abnormal tau, but also the presence of conformationally distinct tau aggregates, namely tau strains. Cryogenic electron microscopy analyses of patient-derived tau filaments have revealed disease-specific ordered tau structures. However, it remains unclear whether the ultrastructural and biochemical properties of tau strains are inherited during the amplification of abnormal tau in the brain. In this study, we investigated template-dependent amplification of tau aggregates using a cellular model of seeded aggregation. Tau strains extracted from human tauopathies caused strain-dependent accumulation of insoluble filamentous tau in SH-SY5Y cells. The seeding activity towards full-length four-repeat tau substrate was highest in CBD-tau seeds, followed by PSP-tau and Alzheimer's disease (AD)-tau seeds, while AD-tau seeds showed higher seeding activity than PiD-tau seeds towards three-repeat tau substrate. Abnormal tau amplified in cells inherited the ultrastructural and biochemical properties of the original seeds. These results strongly suggest that the structural differences of patient-derived tau strains underlie the diversity of tauopathies, and that seeded aggregation and filament formation mimicking the pathogenesis of sporadic tauopathy can be reproduced in cultured cells. Our results indicate that the disease-specific conformation of tau aggregates determines the tau isoform substrate that is recruited for templated amplification, and also influences the prion-like seeding activity.
tau 病是一类以 tau 异常包涵体为特征的神经退行性疾病。具体来说，阿尔茨海默病中的三重复 tau 和四重复 tau、匹克病（PiD）中的三重复 tau、进行性核上性麻痹（PSP）和皮质基底节变性（CBD）中的四重复 tau 形成类似淀粉样的纤维结构，在神经元和/或神经胶质细胞中积累。基于朊病毒假说的异常 tau 的扩增和细胞间传播被认为可以解释 tau 病的发病和进展。最近的研究不仅支持异常 tau 的自我传播，还支持存在构象不同的 tau 聚集物，即 tau 株。对源自患者的 tau 纤维的低温电子显微镜分析揭示了疾病特异性的有序 tau 结构。然而，在大脑中异常 tau 的扩增过程中，tau 株的超微结构和生化特性是否遗传仍不清楚。在这项研究中，我们使用种子聚集的细胞模型研究了 tau 聚集物的模板依赖性扩增。从人类 tau 病中提取的 tau 株导致可溶丝状 tau 在 SH-SY5Y 细胞中的株依赖性积累。在全长四重复 tau 底物中，CBD-tau 种子的引发活性最高，其次是 PSP-tau 和 AD-tau 种子，而 AD-tau 种子对三重复 tau 底物的引发活性高于 PiD-tau 种子。在细胞中扩增的异常 tau 继承了原始种子的超微结构和生化特性。这些结果强烈表明，源自患者的 tau 株的结构差异是 tau 病多样性的基础，并且可以在培养细胞中再现模拟散发性 tau 病发病机制的种子聚集和纤维形成。我们的结果表明，tau 聚集物的疾病特异性构象决定了被招募用于模板扩增的 tau 同工型底物，并且还影响类朊病毒的引发活性。
