Bin1在阿尔茨海默病中介导tau蛋白转运的作用机制

项目名称： Bin1在阿尔茨海默病中介导tau蛋白转运的作用机制

项目编号： No.81500908

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 李红蕾

作者单位： 浙江大学

项目金额： 17.5万元

中文摘要： 阿尔兹海默病（AD）是最常见的神经退行性疾病，严重威胁人类健康。晚发型AD（LOAD）病因不明。近几年的GWAS研究及我们前期的研究发现，BIN1基因上游的多态影响AD发病风险。Bin1在细胞内吞、细胞内转运、细胞骨架调节等方面具有重要作用。近期研究提示，Bin1可能通过与Tau相互作用影响LOAD发病风险。在AD患者大脑中，NFTs聚集以一种类似“病毒传染”的模式播散，按照特定的顺序选择性侵犯影响学习和记忆功能的脑区，其具体播散机制不明。本课题拟利用BIN1过表达或表达下调的细胞模型及突变Tau的AD小鼠模型，探讨Bin1是否在AD中介导Tau蛋白在神经细胞间以及神经元内部的转运，从而达到在AD大脑中“播散”聚集形成NFTs发挥其神经毒性，进而影响LOAD的发病风险。本研究将有助于了解Tau在神经元之间转运的机制，可能为在疾病早期打破Tau病理的播散提供潜在的治疗靶点。

中文关键词： 阿尔茨海默病；桥联蛋白；Tau蛋白；细胞内吞；神经毒性

英文摘要： Alzheimer’s disease (AD) is the most common type of dementia. Its incidence increases with age and has become a major threat to people's health and the society. The cause of late-onset AD (LOAD) is unknown. Recently, many large-scale genome-wide association studies and our previous study results indicate that variants upstream of the BIN1 gene are a genetic determinant of AD susceptibility. Bin1 is involved in numerous cellular processes, including endocytosis, intracellular transport and regulation of cytoskeletal dynamics. Recent studies suggest that Bin1 may influence the risk of LOAD through interaction with microtubule-associated protein Tau. In the brain of patients with AD, abnormal phosphorylated Tau form neurofibrillary tangles （NFTs）. The entorhinal cortex (EC) is the first cortical region affected by NFTs, followed by the hippocampus, and ultimately the neocortex。However, the mechanism underlying interneuronal spread of tau is unknown. In this study, we intend to use cell models that overexpress/ down-regulation of BIN1 and AD mouse model (Tg4510) to study the following questions: 1) Does Bin1 mediate the interneuronal spread of tau and NFTs through endocytosis? 2) Does Bin1 mediate the transport and diffusion of Tau protein in neurons (cell body to axon)? 3) Does Bin1 participate in Tau toxicity? This study will help understand the cellular mechanisms of the spread of tau in AD and may identify potential therapeutic targets for preventing the propagation of tau pathology in the early stage of the disease.

英文关键词： Alzheimer’s disease;Bin1;Tau;Endocytosis;Neurotoxicity