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 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.

Microglia: Agents of the CNS Pro-Inflammatory Response

“…Mechanistically, a CHiPseq experiment revealed that REV-ERBα binds the promoter of NF-κB target genes linked to the inflammatory response such as Traf2 and NF-κB inhibitor beta (Nfkbib), an inhibitor of NF-κB nuclear translocation. A follow-up study in a 5XFAD mouse model of AD revealed that inhibition of REV-ERBα pharmacologically or through genetic knockdown pushed microglia towards a phagocytic phenotype as measured by an increase in Aβ clearance and a decrease in plaque deposition [257].…”

Evaluating Circadian Dysfunction in Mouse Models of Alzheimer’s Disease: Where Do We Stand?

“…Wu et al (2018) showed a slight phase delay and decreased expression of Per1/2 in the SCN of 3xTG mice, while Ma et al (2016) showed altered rhythms in hippocampal Bace2 and Apoe mRNA. Other studies in AD models have examined clock gene expression at one or two time points throughout the circadian cycle, usually early morning and early evening, in some case showing a loss of variation in AD mice (Duncan et al, 2012;Bellanti et al, 2017;Stevanovic et al, 2017;Lee et al, 2020). While these can be used to make general conclusions, it is difficult to interpret if clock genes are changing amplitude, or if there is just a difference in phase of expression of that particular gene.…”

REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis

“…Previous work from our group shows that deletion of BMAL1 or its downstream target REV-ERBα causes neuroinflammation and impaired brain functional connectivity ( Griffin et al, 2019 ; Musiek et al, 2013 ). Diminished BMAL1 and REV-ERBα expression have also been described in mouse models of Alzheimer’s disease (AD)( Lee et al, 2020 ; Stevanovic et al, 2017 ). In AD, memory-associated, synapse-rich regions such as the hippocampus are affected early in the disease course ( Braak et al, 2006 ).…”