阿尔茨海默病（AD）是一种最常见的神经退行性疾病，属于复杂的多基因遗传病。近期有研究报道TREM1基因rs6910730多态性和人群的认知下降速度及脑内AD相关Aβ病理显著关联，我们发现TREM1基因rs6910730G变异可改变单核细胞表面TREM1的表达水平及其吞噬Aβ的能力，TREM1可易化小胶质细胞对Aβ的吞噬功能，该结果发表在Acta Neuropathol。本项目拟在前期研究的基础上，对汉族AD患者和健康对照的TREM1关键区域进行深度测序，筛选出AD易感位点，以全面揭示汉族人群TREM1基因变异与AD的易感关系。此外，我们拟以原代培养小胶质细胞、APP/PS1转基因小鼠和TREM1-/-小鼠等生物学模型为研究对象，从细胞水平和基因敲除动物水平研究TREM1对小胶质细胞的激活状态及功能调控和对AD病理特征及认知障碍的影响，以全面探讨TREM1参与AD病理进程的分子机制。

Alzheimer’s disease, as a kind of complex polygenic heredity disease, is the most common neurodegenerative disease. A recent study indicated a close association between triggering receptor expressed on myeloid cells 1 (TREM1) and late-onset Alzheimer’s disease (LOAD), as its intronic variant rs6910730G was related to Aβ pathology of LOAD and aging-related cognitive decline, suggesting TREM1 represents an important susceptibility gene for LOAD. In our preliminary studies, we provided the first evidence that the reduction of Aβ phagocytosis caused by rs6910730G was likely ascribed to a decreased monocytic TREM1 expression. Meanwhile, we demonstrated that TREM1 was able to modulate the microglial Aβ clearance in brain that was implicated in Aβ pathogenesis. Our results were published in Acta Neuropathol. Based on these findings, we intend to investigate TREM1 using High-Throughput Sequencing to identify risk variants for LOAD in a large Han Chinese cohort. In addition, to fully elucidate the role of TREM1 in AD pathogenesis, we intend to use primary microglia, APP/PS1 mice and TREM1-/- mice to reveal its modulation on function of microglia as well as AD-related neuropathology and cognitive impairment. The completion of this project will provide theoretic support for early warning and diagnosis of AD in Han Chinese, and will offer novel target for therapies and drug development of this disease via uncovering its underlying pathogenesis.