Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer's disease
Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer's disease
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DOI：
10.1111/acel.13078
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发表时间：
2019-12-04
期刊：
影响因子：
7.8
通讯作者：
Yoon, Seung-Yong
中科院分区：
文献类型：
--
作者：
Lee, Jiyeon;Kim, Do-Eun;Yoon, Seung-Yong
昼夜节律系统是治疗阿尔茨海默病（AD）的一个有希望的新治疗靶点。虽然已知AD患者有异常的昼夜节律和睡眠障碍，但分子钟在调节淀粉样蛋白- β (A β)病理中的作用仍然知之甚少。在这里，我们探讨了昼夜节律抑制因子REV-ERB α和β如何影响小鼠小胶质细胞中A β的清除。我们发现，在昼夜节律时间4 (CT4)，小胶质细胞表达了更高水平的主时钟蛋白BMAL1，并且比CT12更快地吞噬原纤维A β (1-42) （fA β(1-42)）。BMAL1直接驱动REV-ERB蛋白的转录，这与小胶质细胞的激活有关。有趣的是，用小分子拮抗剂SR8278抑制REV-ERBs或基因敲低REV-ERBs会加速小胶质细胞对fA β(1-42)的摄取，并增加BMAL1的转录。SR8278还通过增加P2Y（12）受体的表达，促进小胶质细胞向吞噬细胞m2样表型极化。最后，在AD的5XFAD模型中，Rev-erb α的组成性缺失减少了淀粉样斑块的数量和大小，并阻止了斑块相关的疾病相关小胶质细胞标志物（包括TREM2、CD45和Clec7a）的增加。总之，我们的工作提出了一种通过靶向REV-ERBs来控制a β清除和神经炎症的新策略，并为REV-ERBs在AD中的作用提供了新的见解。
A promising new therapeutic target for the treatment of Alzheimer's disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid-beta (A beta) pathology is still poorly understood. Here, we explored how the circadian repressors REV-ERB alpha and beta affected A beta clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary A beta(1-42) (fA beta(1-42)) than at CT12. BMAL1 directly drives transcription of REV-ERB proteins, which are implicated in microglial activation. Interestingly, pharmacological inhibition of REV-ERBs with the small molecule antagonist SR8278 or genetic knockdown of REV-ERBs-accelerated microglial uptake of fA beta(1-42) and increased transcription of BMAL1. SR8278 also promoted microglia polarization toward a phagocytic M2-like phenotype with increased P2Y(12) receptor expression. Finally, constitutive deletion of Rev-erb alpha in the 5XFAD model of AD decreased amyloid plaque number and size and prevented plaque-associated increases in disease-associated microglia markers including TREM2, CD45, and Clec7a. Altogether, our work suggests a novel strategy for controlling A beta clearance and neuroinflammation by targeting REV-ERBs and provides new insights into the role of REV-ERBs in AD.