CDK5-LPL信号通路促进Aβ吞噬及其调控Tau蛋白磷酸化修饰研究

项目名称： CDK5-LPL信号通路促进Aβ吞噬及其调控Tau蛋白磷酸化修饰研究

项目编号： No.31470807

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物物理、生化与生物分子学、生物力学与组织工程

项目作者： 纪建国

作者单位： 北京大学

项目金额： 85万元

中文摘要： 阿尔茨海默病（AD）严重危害人们的健康，其发病机制尚不清楚并缺乏有效的治疗药物。病理检查发现脑组织中存在由Aβ淀粉样蛋白组成的老年斑、神经炎性斑块和Tau蛋白组成的神经纤维缠结等特征，并在Aβ斑块中发现脂蛋白、补体因子等蛋白以及在Aβ周围活化的小胶质细胞。小胶质细胞在Aβ吞噬和清除过程中起了关键的作用。我们前期研究中首次发现细胞周期依赖激酶CDK5的调节亚基p25和脂蛋白酶LPL在Aβ吞噬过程中上调，导致CDK5活性升高，增强小胶质细胞吞噬Aβ的能力，但CDK5在Aβ吞噬与Tau蛋白过度磷酸化交叉调控作用机制研究未见报道。本课题拟利用细胞、转基因动物模型、临床样本、高通量质谱技术平台，针对Aβ吞噬、CDK5调控的磷酸化修饰，系统研究小胶质细胞在Aβ吞噬过程中蛋白质的动态变化、CDK5功能及其调控Tau蛋白磷酸化修饰的信号网络，发现新的调控靶标和作用机制，为AD发病机制和治疗提供新的依据。

中文关键词： 阿尔茨海默病；细胞周期依赖激酶CDK5；小胶质细胞；Aβ吞噬；Tau蛋白过度磷酸化

英文摘要： Alzheimer's disease (AD) seriously threatens human's health and the mechanism under its pathogenesis still keeps unclear. Until now, there is no cure or effective treatment drug for AD. Pathological examination revealed the presence of senile plaques consisting of amyloid Aβ, neuritic plaques, and neurofibrillary tangles which is full of Tau proteins in the human brain tissue. In addition, researchers also found lipoprotein, Complement factor in Aβ plaques and activated microglia surrounding Aβ. Microglia plays an important role in the Aβ phagocytosis and clearance. However, it reported less about research on the mechanism under this process. In the previous study, we found that p25 and LPL were increased in the process of Aβ phagocytosis and lead to enhanced CDK5 activity and the phagocytosis ability in microglia for the first time, but the signaling pathway and the mechanism of cross-talk between Aβ phagocytosis and Tau hyper-phosphorylation regulated by CDK5 are kept promising and remain unclear. For Aβ deposition and CDK5 regulatory phosphorylation modification, we intend to use cell line, transgenic animal model, clinical samples, and high-throughput mass spectrometry platform to systematically study the dynamics in the microglia phagocytosis of Aβ, CDK5 function and the signaling network which regulates the phosphorylation modification of Tau protein, then figure out the detailed mechanism and new therapeutic targets, and provide new evidence for AD pathogenesis and therapy.

英文关键词： Alzheimer's disease;cell cycle dependent kinase 5-CDK5;microglia;Aβ phagocytosis;Tau hyperphosphorylation