TREM2的功能效应及其突变体参与阿尔茨海默病发生的分子机制研究

阿尔茨海默病（AD）是一种中枢神经系统原发性神经退行性疾病。研究发现，小胶质细胞上特异性表达的髓细胞触发受体-2（TREM2）编码区突变增加AD患病风险约3倍，与公认的载脂蛋白apoEε4风险因子相近。但是，TREM2的功能效应及其突变体参与AD发生的分子机制尚不明确。我们前期发现，TREM2杂合缺失的AD模型小鼠脑组织中淀粉样斑块周围小胶质细胞显著减少，斑块周围神经元营养不良；TREM2表达和/或功能异常，显著影响小胶质细胞的活化、迁移、吞噬等功能状态，同时影响神经元突触功能等。拟进一步以原代培养小胶质细胞和神经元、5×FAD小鼠、Trem2-/-小鼠和TREM2的R47H突变小鼠等模型为研究对象，深入剖析TREM2调控的小胶质细胞对Aβ淀粉样蛋白的包裹屏障作用机制、以及对神经突触功能调控的分子机制，并揭示TREM2突变体参与AD发病的机制。为AD等神经退行性疾病的治疗提示新的分子靶点。

Alzheimer's disease (AD) is a major neurodegenerative disease, whose etiology has yet to be fully determined. Recent studies have identified the triggering receptor expressed on myeloid cells-2 (TREM2) gene as a strong genetic risk factor for AD. Mutations in TREM2, a trans-membrane receptor expressed in microglia, are associated with increased risk for AD comparable to that of apoEε4. However, the physiological function of TREM2 and the molecular mechanism underlying TREM2 mutation-induced disease pathogenesis remain elusive. Our recent preliminary studies have shown that TREM2 deficiency leads to reduced microgliosis and neuritic dystrophy in 5XFAD mice. Furthermore, depletion of TREM2 expression in microglia leads to compromised functions of microglia in activation, migration and phagocytosis，as well as abnormal electrophysiological activity at synapses. In the current proposal, we plan to use primary cell cultures and animal models to determine the physiological role of TREM2 in regulating microglia phagocytosis and barrier function, and in modulating neuron morphology and synaptic functions. Moreover, we will investigate how TREM2 R47H mutation contributes cognitive decline, synaptic dysfunctions and amyloid pathology in the 5XFAD mice. Together, our proposed studies will uncover molecular and cellular mechanisms associated with TREM2-mediated protection against AD development and cognitive decline, thereby nominating new strategies for AD therapy.