TREM1和汉族人群阿尔茨海默病的关联分析及其致病机制研究

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.

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。

本项目完成了对汉族人群TREM1基因的深度测序，并完成了TREM1基因多态性与AD风险的关联性分析，明确了TREM1基因上的一个新型、独立的遗传位点rs2062323和汉族人群罹患AD的风险相关。TREM1基因上的rs2062323位点的最小等位基因T可降低汉族人群罹患AD的风险。此外，还明确了rs2062323和脑脊液AD生物标志物sTREM2之间的关联性。以上关联性在非汉族人群中得到了验证。进一步探讨了TREM1基因作为AD 药物干预靶点的潜在价值，为AD 的防治提供了新的选择。此外，动物实验结果显示不管是在C57小鼠还是在APP/PS1小鼠上敲除Trem1基因，小胶质细胞的比例显著降低，星形胶质细胞的比例显著升高。小胶质细胞差异基因富集分析显示Trem1基因可能通过氧化磷酸化通路参与AD相关的病理生理过程。课题进行期间项目相关成果在NEUROTOXICITY RESEARCH、Frontiers in Neuroscience、Annals of Translational Medicine、Journal of Alzheimer’s Disease等国际顶级杂志共发表SCI 收录论文9 篇，累计影响因子39.352 分。本项目研究成果荣获山东省科技进步二等奖1 项，山东省科技进步三等奖1 项，山东省医学科技奖三等奖1 项。本项目支持下，项目多位参与人员受邀参加美国阿尔茨海默病协会国际会议（AAIC）。依托本项目前后期工作的成果支持，参与人员谭辰辰博士、万宇博士和徐伟博士荣获“齐鲁卫生与健康杰出青年人才”称号。本项目共培养博士3 名，硕士6 名。本项目研究成果已经在多家大型医院推广应用，具有显著的社会效益。