目前，阿尔茨海默病（AD）发病机制尚不完全清楚。我们前期实验首次发现趋化因子样受体1（CMKLR1）是Aβ的功能性受体，其激活能增加小胶质细胞，星形胶质细胞及神经元对Aβ的吞噬，降低Tau蛋白的磷酸化。因此，我们提出“CMKLR1是参与AD发生发展的重要调节分子”假说：一些刺激因素诱导小胶质细胞激活其释放的炎症因子作用神经元导致Aβ沉积及Tau磷酸化；同时释放Chemerin直接作用神经元，或作用小胶质细胞产生某种因子作用神经元，降低神经元内Aβ产生及Tau磷酸化；小胶质细胞激活还导致CMKLR1增加，使小胶质细胞向Aβ聚集并吞噬Aβ；星形胶质细胞及神经元上的CMKLR1也参与Aβ的吞噬和降解。本项目在前期工作基础上，采用转基因小鼠及STZ侧脑室注射建立两种AD模型，通过CMKLR1基因缺失和配体激活探究CMKLR1是否参与AD的发生和发展；最后，采用原代细胞验证CMKLR1作用机制。

Alzheimer’s disease (AD) is a severe neurodegenerative disease of the central nervous system, of which the pathogenesis is not very clear. Our previous experiment found that Chemokine-like receptor 1 (CMKLR1) is a functional receptor for Aβ. CMKLR1 activation can induce the endocytosis of Aβ from primary cultured microglia, astrocytes and neurons and can also reduce the tau phosphorylation in neurons. Therefore, we propose that CMKLR1 plays a key role in the occurrence and development of AD: Microglia and astrocytes activated in AD brain, and the pro-inflammatory factors released by activated microglia or astrocytes induce the accumulation of Aβ and tau hyperphosphorylation in neurons. Activated microglia or astrocytes also release chemerin, which reduces the production of Aβ and tau phosphorylation by activating CMKLR1 on neurons directly, or on microglia indirectly. In addition, increased CMKLR1 expressed on microglia, astrocytes or neurons induced the endocytosis and clearence of Aβ. Based on our previous work, two AD mouse model with CMKLR1 deficiency will be established in here to verify that if CMKLR1 is involved in the occurrence and development of AD, if CMKLR1 participates in the reduction of Aβ accumulation and tau hyperphosphorylation. Finally, the mechanism of role of CMKLR1 will be further explored in vitro by using the primary cell culture system.