Department of Chemistry, Massachusetts Institute of Technology, 170 Albany Street, Cambridge, MA, 02139, USA.
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA.
Nat Commun. 2022 May 27;13(1):2967. doi: 10.1038/s41467-022-30585-0.
Alzheimer's disease (AD) is defined by intracellular neurofibrillary tangles formed by the microtubule-associated protein tau and extracellular plaques formed by the β-amyloid peptide. AD tau tangles contain a mixture of tau isoforms with either four (4R) or three (3R) microtubule-binding repeats. Here we use solid-state NMR to determine how 4R and 3R tau isoforms mix at the molecular level in AD tau aggregates. By seeding differentially isotopically labeled 4R and 3R tau monomers with AD brain-derived tau, we measured intermolecular contacts of the two isoforms. The NMR data indicate that 4R and 3R tau are well mixed in the AD-tau seeded fibrils, with a 60:40 incorporation ratio of 4R to 3R tau and a small homotypic preference. The AD-tau templated 4R tau, 3R tau, and mixed 4R and 3R tau fibrils exhibit no structural differences in the rigid β-sheet core or the mobile domains. Therefore, 4R and 3R tau are fluently recruited into the pathological fold of AD tau aggregates, which may explain the predominance of AD among neurodegenerative disorders.
阿尔茨海默病（AD）的定义是由微管相关蛋白 tau 形成的细胞内神经原纤维缠结和由 β-淀粉样肽形成的细胞外斑块。AD tau 缠结包含具有四（4R）或三（3R）个微管结合重复的 tau 异构体的混合物。在这里，我们使用固态 NMR 来确定 AD tau 聚集体中 4R 和 3R tau 异构体如何在分子水平上混合。通过用 AD 脑衍生的 tau 接种差异同位素标记的 4R 和 3R tau 单体，我们测量了两种异构体的分子间接触。NMR 数据表明，4R 和 3R tau 在 AD tau 接种的原纤维中很好地混合，4R 与 3R tau 的掺入比例为 60:40，并且具有较小的同种型偏好。AD-tau 模板化的 4R tau、3R tau 和混合的 4R 和 3R tau 原纤维在刚性 β-片层核心或可移动结构域中没有结构差异。因此，4R 和 3R tau 被流畅地招募到 AD tau 聚集体的病理折叠中，这可能解释了 AD 在神经退行性疾病中的优势。
