Rong Zhouyi, Cheng Baoying, Zhong Li, Ye Xiaowen, Li Xin, Jia Lin, Li Yanfang, Shue Francis, Wang Na, Cheng Yiyun, Huang Xiaohua, Liu Chia-Chen, Fryer John D, Wang Xin, Zhang Yun-Wu, Zheng Honghua
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, China.
Shenzhen Research Institute, Xiamen University, Shenzhen, China.
FASEB J. 2020 Aug;34(8):10984-10997. doi: 10.1096/fj.202000550RR. Epub 2020 Jul 1.
Mutation of Triggering receptor expressed on myeloid cells 2 (TREM2) impairs the response of microglia to amyloid-β (Aβ) pathology in Alzheimer's disease (AD), although the mechanism governing TREM2-regulated microglia recruitment to Aβ plaques remains unresolved. Here, we confirm that TREM2 mutation attenuates microglial migration. Then, using Trem2 mice and an R47H variant mouse model for AD generated for this study, we show that TREM2 deficiency or the AD-associated R47H mutation results in inhibition of FAK and Rac1/Cdc42-GTPase signaling critical for cell migration. Intriguingly, treatment with CN04, a Rac1/Cdc42-GTPase activator, partially enhances microglial migration in response to oligomeric Aβ in Trem2 or R47H microglia both in vitro and in vivo. Our study shows that the dysfunction of microglial migration in the AD-associated TREM2 R47H variant is caused by FAK/Rac1/Cdc42 signaling disruption, and that activation of this signaling ameliorates impaired microglial migration response to Aβ , suggesting a therapeutic target for R47H-bearing patients with high risk of AD.
髓系细胞触发受体2（TREM2）的突变会损害小胶质细胞对阿尔茨海默病（AD）中淀粉样β蛋白（Aβ）病理的反应，尽管TREM2调节小胶质细胞向Aβ斑块募集的机制仍未明确。在此，我们证实TREM2突变会减弱小胶质细胞的迁移。然后，使用本研究构建的Trem2基因敲除小鼠和AD相关R47H变异小鼠模型，我们发现TREM2缺陷或AD相关的R47H突变会导致对细胞迁移至关重要的粘着斑激酶（FAK）和Rac1/Cdc42 - GTP酶信号传导受到抑制。有趣的是，用Rac1/Cdc42 - GTP酶激活剂CN04处理，在体外和体内均可部分增强Trem2或R47H小胶质细胞对寡聚Aβ的迁移反应。我们的研究表明，AD相关TREM2 R47H变异中小胶质细胞迁移功能障碍是由FAK/Rac1/Cdc42信号传导破坏引起的，并且该信号传导的激活可改善小胶质细胞对Aβ受损的迁移反应，这为具有高AD风险的携带R47H的患者提供了一个治疗靶点。
