Activation of FAK/Rac1/Cdc42-GTPase signaling ameliorates impaired microglial migration response to A beta(42)in triggering receptor expressed on myeloid cells 2 loss-of-function murine models
Activation of FAK/Rac1/Cdc42-GTPase signaling ameliorates impaired microglial migration response to A beta(42)in triggering receptor expressed on myeloid cells 2 loss-of-function murine models
复制标题
FAK/Rac1/Cdc42-GTPase 信号传导的激活可改善骨髓细胞表达的触发受体中受损的小胶质细胞对 A beta(42) 的迁移反应 2 功能丧失小鼠模型
DOI：
10.1096/fj.202000550rr
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发表时间：
2020
期刊：
影响因子：
4.8
通讯作者：
Zheng Honghua
中科院分区：
文献类型：
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作者：
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
髓样细胞2（TREM 2）上表达的触发受体突变会损害阿尔茨海默病（AD）中小胶质细胞对淀粉样蛋白β（A β）病理的反应，尽管TREM 2调节小胶质细胞招募到A β斑块的机制仍未得到解决。在这里，我们证实TREM2突变减弱小胶质细胞迁移。然后，使用Trem2（-/-）小鼠和本研究产生的AD的R47H变体小鼠模型，我们表明TREM2缺陷或AD相关的R47H突变导致FAK和Rac1/Cdc42-GTdR信号传导的抑制，这些信号传导对细胞迁移至关重要。有趣的是，用CN 04（Rac 1/Cdc42-GT β激活剂）处理在体外和体内均部分增强了小胶质细胞响应寡聚A β（42）inTrem2（-/-）或R47 H小胶质细胞的迁移。我们的研究表明，AD相关TREM2 R47 H变体中的小胶质细胞迁移功能障碍是由FAK/Rac 1/Cdc42信号传导中断引起的，并且该信号传导的激活改善了受损的小胶质细胞对A β的迁移反应（42），这表明具有AD高风险的R47 H携带患者的治疗靶点。
Mutation of Triggering receptor expressed on myeloid cells 2 (TREM2) impairs the response of microglia to amyloid-beta (A beta) pathology in Alzheimer's disease (AD), although the mechanism governing TREM2-regulated microglia recruitment to A beta plaques remains unresolved. Here, we confirm that TREM2 mutation attenuates microglial migration. Then, usingTrem2(-/-)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 A beta(42)inTrem2(-/-)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 A beta(42), suggesting a therapeutic target for R47H-bearing patients with high risk of AD.