Bin1在阿尔茨海默病中介导tau蛋白转运的作用机制

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.

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。

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。 本项目利用BIN1过表达、表达下调的细胞模型及AD小鼠的海马原代神经元细胞模型，探讨了Bin1在AD 中介导Tau蛋白在神经细胞间转运的机制。我们发现：1. AD患者血清中Bin1 mRNA表达明显高于正常对照，Bin1过表达后Tau蛋白表达亦增加，且Bin1蛋白与Tau蛋白在细胞内共定位，说明两者间存在相互作用；2. Bin1不参与摄取细胞外液中的Tau蛋白；3. Bin1蛋白通过外泌体途径进行主动分泌，可能参与Tau蛋白在细胞间的转运。 本项目初步揭示了 Bin1介导Tau在神经细胞间转运的机制，从而为在疾病早期打破Tau病理的播散提供潜在的干预靶点和治疗思路。