Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer's disease. Issue 2 (4th December 2019)

• Record Type: Journal Article
• Authors: Lee, Jiyeon; Kim, Do Eon; Griffin, Percy; Sheehan, Patrick W.; Kim, Dong‐Hou; Musiek, Erik S; Yoon, Seung‐Yong
• Is Part Of: Aging cell. Volume 19:Issue 2(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-12-04
• Subjects: Alzheimer's disease -- circadian -- microglia -- REV‐ERBs -- SR8278; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.13078
• Languages: English
• ISSNs: 1474-9718

Abstract

Abstract: 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 Aβ1‐42 (fAβ1‐42 ) 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 fAβ1‐42 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. Abstract : Genetic and pharmacological inhibition of REV‐ERBα is markedly increased microglial phagocytosis of Aβ by modulating P2Y12R expression with induction of Aβ internalization‐related receptors, leading to the M2 polarization in vitro and in vivo.