Aβ and tau prion-like activities decline with longevity in the Alzheimer's disease human brain
Aβ and tau prion-like activities decline with longevity in the Alzheimer's disease human brain
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DOI：
10.1126/scitranslmed.aat8462
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发表时间：
2019-05-01
影响因子：
17.1
通讯作者：
Prusiner, Stanley B.
中科院分区：
文献类型：
--
作者：
Aoyagi, Atsushi;Condello, Carlo;Prusiner, Stanley B.
阿尔茨海默病(AD)的特征是聚集Aβ斑块和由过度磷酸化的tau组成的神经原纤维缠结。我们开发了使用人类胚胎肾脏-293T细胞的灵敏细胞分析，以定量AD或其他神经退行性疾病患者脑组织样本中细胞内自繁殖的Aβ构象。阿尔茨海默病患者的死后脑组织中有相当数量的病理性Aβ构象。80岁以上的人有最低数量的蛋白样蛋白Aβ和磷酸化tau。出乎意料的是，尽管总不溶性tau的数量增加了，但自繁殖tau构象的减少却与寿命有关。当校正了不溶性tau的丰度后，死后AD大脑匀浆在细胞分析中诱导错误折叠tau的能力显示出随着寿命的延长而指数下降，在37至99岁的年龄范围内半衰期约为10年。因此，我们的发现表明，AD患者的寿命与病理tau构象的丰富程度呈负相关。我们的细胞分析可以应用于临床研究的患者选择以及AD新药和诊断的开发。
The hallmarks of Alzheimer's disease (AD) are the accumulation of A beta plaques and neurofibrillary tangles composed of hyperphosphorylated tau. We developed sensitive cellular assays using human embryonic kidney-293T cells to quantify intracellular self-propagating conformers of A beta in brain samples from patients with AD or other neurodegenerative diseases. Postmortem brain tissue from patients with AD had measurable amounts of pathological A beta conformers. Individuals over 80 years of age had the lowest amounts of prion-like A beta and phosphorylated tau. Unexpectedly, the longevity-dependent decrease in self-propagating tau conformers occurred in spite of increasing amounts of total insoluble tau. When corrected for the abundance of insoluble tau, the ability of postmortem AD brain homogenates to induce misfolded tau in the cellular assays showed an exponential decrease with longevity, with a half-life of about one decade over the age range of 37 to 99 years. Thus, our findings demonstrate an inverse correlation between longevity in patients with AD and the abundance of pathological tau conformers. Our cellular assays can be applied to patient selection for clinical studies and the development of new drugs and diagnostics for AD.