CD2AP介导细胞骨架-内体-溶酶体途径在阿尔茨海默病发病中的作用及机制研究

阿尔茨海默病（AD）是最常见的神经变性病，其病因和发病机制仍不明。申请人前期研究发现CD2AP是散发性AD的易感基因，且其在AD患者外周血mRNA表达水平较正常对照显著下降，前期构建的CD2AP神经元条件性敲除小鼠在9月龄时出现焦虑、抑郁和皮层磷酸化Tau蛋白升高等AD早期表现。蛋白质组学研究发现CD2AP下调或上调后细胞骨架-内体-溶酶体途径相关蛋白出现显著变化，且观察到CD2AP敲除或敲减后出现细胞骨架复杂度降低和内体形态异常。结合既往研究显示细胞骨架-内体-溶酶体途径和AD发病密切相关，我们提出本课题的科学假说：CD2AP介导细胞骨架-内体-溶酶体途径参与AD发病。我们拟在前期研究基础上，从分子，细胞，组织和转基因动物水平等多层次探讨CD2AP对细胞骨架-内体-溶酶体途径的调控作用及其在AD发病中的具体作用机制，本课题的研究将有助于阐明AD的发病机制，为AD的治疗提供新的靶点。

Alzheimer's disease (AD) is the most common neurodegenerative disease, and its etiology and pathogenesis remains unclear. In previous study, we found CD2AP was a susceptibility gene for sporadic AD, and its mRNA expression level in peripheral blood of AD patients was significantly lower than that of normal elderly controls. 9 months old CD2AP neuron conditional knockout mice demonstrated early manifestations of AD, such as anxiety, depression and elevated phosphorylated Tau level in cortex. Further proteomic analysis found CD2AP knockdown or up-regulation caused proteins involved in cytoskeleton-endosome-lysosomal pathway significantly changed. In addition, significant abnormalities in the neuronal skeleton and endosomal morphology were observed in CD2AP knockout or knockdown neurons and cell lines. Combine with previous studies which showed the cytoskeleton-endosome-lysosomal pathway was related to the pathogenesis of AD, we propose the scientific hypothesis of this project: CD2AP participates in the pathogenesis of AD by mediating cytoskeleton-endosomal-lysosome pathway. Our project will deeply explore the role of CD2AP on the cytoskeleton-endosome-lysosomal pathway and the mechanisms underlying the pathogenesis of AD from the molecular, cell, tissue and transgenic animal levels on the basis of our original discovery and results. Our project will help to elucidate the pathogenesis of AD, providing new potential targets for the treatment of AD.