Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer's disease.,Aging Cell

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Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer's disease.
Aging Cell ( IF 8.0 ) Pub Date : 2019-12-04 , DOI: 10.1111/acel.13078
Jiyeon Lee _{1,

2} , Do Eon Kim ₁ , Percy Griffin ₂ , Patrick W Sheehan ₂ , Dong-Hou Kim ₁ , Erik S Musiek ₂ , Seung-Yong Yoon ₁

Affiliation

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 (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV‐ERBα and β affected Aβ 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 Aβ_1‐42 (fAβ_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 fAβ_1‐42 and increased transcription of BMAL1. SR8278 also promoted microglia polarization toward a phagocytic M2‐like phenotype with increased P2Y₁₂ receptor expression. Finally, constitutive deletion of Rev‐erbα 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 Aβ clearance and neuroinflammation by targeting REV‐ERBs and provides new insights into the role of REV‐ERBs in AD.

中文翻译：

在阿尔茨海默病 5XFAD 小鼠模型中，抑制 REV-ERB 可刺激小胶质细胞淀粉样蛋白 -β 清除并减少淀粉样斑块沉积。

治疗阿尔茨海默病（AD）的一个有前景的新治疗靶点是昼夜节律系统。尽管已知 AD 患者昼夜节律异常并患有睡眠障碍，但分子钟在调节淀粉样蛋白 - β (Aβ) 病理学中的作用仍知之甚少。在这里，我们探讨了昼夜节律抑制因子 REV-ERBα 和 β 如何影响小鼠小胶质细胞中的 Aβ 清除。我们发现，在昼夜节律时间 4 (CT4)，小胶质细胞表达的主时钟蛋白 BMAL1 水平比 CT12 更高，并且吞噬纤维 Aβ _1-42 (fAβ _1-42 ) 的速度更快。 BMAL1 直接驱动 REV-ERB 蛋白的转录，该蛋白与小胶质细胞激活有关。有趣的是，用小分子拮抗剂 SR8278 对 REV-ERB 进行药理学抑制或 REV-ERB 基因敲除可加速小胶质细胞对 fAβ _1-42的摄取并增加 BMAL1 的转录。 SR8278 还促进小胶质细胞极化为吞噬细胞 M2 样表型，并增加 P2Y ₁₂受体表达。最后，AD 5XFAD 模型中 Rev-erbα 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记物（包括 TREM2、CD45 和 Clec7a）的增加。总而言之，我们的工作提出了一种通过靶向 REV-ERB 来控制 Aβ 清除和神经炎症的新策略，并为 REV-ERB 在 AD 中的作用提供了新的见解。

更新日期：2019-12-04

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