A study on the molecular mechanisms of neurodegeneration induced by high-mass amyloid-beta assembly, amylospheroids (ASPD)

淀粉样蛋白（Abeta）在阿尔茨海默病（AD）中起着核心作用。为了阐明致病性β低聚物及其导致神经变性的神经元靶点的分子特征，我们之前从阿尔茨海默病患者的大脑中分离出了被称为淀粉样球体（ASPD）的高毒性β组装体。患者源性ASPD对人类成熟神经元具有毒性，其在AD易感区域的数量与AD的病理严重程度密切相关。在这项研究中，我们发现反ASPD的神经毒性需要Ca2+内流。我们还发现电压门控钙通道（VGCC）参与ASPD的神经毒性。有趣的是，ASPD诱导的异常Ca2+超载激活了两种tau蛋白激酶，并增加了tau蛋白的磷酸化。重要的是，我们发现ASPD与成熟神经元表面的ASPD靶蛋白结合会损害其活性，导致上述异常的Ca2+稳态和严重的神经退行性变。

Amyloid beta protein (Abeta) plays a central role in Alzheimer's disease (AD). To elucidate the molecular identities of pathogenic Abeta oligomers and their neuronal targets responsible for neurodegeneration, we have previously isolated highly toxic Abeta assemblies termed amylospheroids (ASPD) from AD patient brains. Patient-derived ASPD were toxic to human mature neurons and their amount in AD susceptible regions well correlated with pathological severity of AD. In this study, we found that ASPD neurotoxicity requires Ca2+ influx. We also found that voltage gated calcium channels (VGCC) are involved in ASPD neurotoxicity. Interestingly, the abnormal Ca2+ overload induced by ASPD activated two tau protein kinases, and increased the phosphorylation of tau. Importantly, we found that ASPD-binding to the ASPD target protein on mature neuronal surface impairs its activity, responsible for the above abnormal Ca2+ homeostasis and to the severe neurodegeneration.