MS4A6A和汉族人群阿尔茨海默病的关联分析及其致病机制研究

欧美大规模GWAS研究发现MS4A6A为AD新的易感基因，我们前期率先证实MS4A6A与汉族人群AD风险亦存在关联，但其遗传变异的精细作图及参与AD的机制尚不明确。我们还发现脑内MS4A6A与可调控小胶质细胞功能的TREM2表达水平高度一致，其AD风险位点显著调控可溶性TREM2水平。因此我们提出“MS4A6A可通过影响小胶质细胞功能、活性状态及对Aβ的吞噬活性而参与AD发生”这一假说。在本项目中，我们拟对汉族人群MS4A6A区域进行深度测序，揭示汉族人群MS4A6A遗传变异与AD的易感关系。此外，我们以小胶质细胞及APP/PS1小鼠为研究对象，结合基因敲除和过表达技术对Ms4a6d（MS4A6A的小鼠同源基因）进行靶向调控，从细胞和活体水平研究MS4A6A对小胶质细胞的调控和对AD病理及认知的影响，以阐明MS4A6A参与AD的机制。本项目的完成对深入阐释AD发生的分子遗传机制有重要价值。

MS4A6A is a novel susceptible gene for AD in the Caucasian population. In our preliminary studies, we provide the first concrete evidence that MS4A6A variants are associated with the risk of AD in the Han Chinese population. We also find the expression of MS4A6A in the human brain is highly correlated with TREM2, which could regulate the function of microglia, whereas the CSF levels of soluble TREM2 is regulated by AD risk variants in MS4A6A. However, the presence of potentially functional variations and the mechanisms of MS4A6A involvement in AD remains unknown. In this project, we hypothesize that MS4A6A participates in AD pathogenesis through modulation of microglial activation and function. Our aim is to investigate MS4A6A using High-Throughput Sequencing to identify risk variants for LOAD in a large Han Chinese cohort and to elucidate the role of MS4A6A in AD pathogenesis fully. Furthermore, we also intend to initiate in vitro and in vivo studies, using knock-out and over-expression technologies in primary microglia and APP/PS1 mice, in order to determine the role of MS4A6A in microglia modulation and AD-related neuropathology and cognitive impairment. This project will provide significant values for uncovering the underlying genetic mechanisms of AD.