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

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 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 mol

SUBMITTER: Lee J 

PROVIDER: S-EPMC6996949 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature