Role of Intracellular ABeta in Tau Pathology

描述（由申请人提供）：由于已经证明阿尔茨海默病（AD）大脑中神经原纤维缠结（NFT）数量的增加与认知功能的下降有关，阐明缠结病理启动的机制可能会揭示阿尔茨海默病神经元易感性的重要信息。提出的研究是基于这样的假设，即在天冬氨酸-421位点的tau蛋白的caspase裂解是AD NFT病理进化中的一个关键事件。虽然我们最近的研究表明，caspase切割的tau蛋白在体外非常容易形成细丝，并且与AD NFT病理的早期免疫组织化学标志物有关，但导致tau蛋白caspase蛋白水解的启动机制尚不清楚。拟议研究的目的是研究体外细胞内β -淀粉样蛋白（ABeta）作为导致tau蛋白的caspase蛋白水解的级联反应的潜在发起者的作用。

DESCRIPTION (provided by applicant): Since it has been demonstrated that increasing neurofibrillary tangle (NFT) number in the Alzheimer's disease (AD) brain correlates with reduced cognitive function, elucidating the mechanisms by which tangle pathology is initiated may reveal important information regarding neuronal vulnerability in AD. The proposed studies are based upon the hypothesis that caspase-cleavage of tau at aspartate-421 is a key event in the evolution of AD NFT pathology. While our recent research efforts demonstrate that caspase-cleaved tau is very prone to filament formation in vitro and is associated with early immunohistochemical markers of AD NFT pathology, the initiating mechanisms leading to caspase proteolysis on tau are unknown. The goals of the proposed studies are to investigate the role of in vitro intracellular beta-amyloid (ABeta) as a potential initiator of the cascade leading to caspase proteolysis of tau.