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.
Highlights
Circadian rhythms such as the sleep–wake cycle are internal rhythms that exist on a 24-hr period
Because amyloid plaque deposition is associated with the accumulation of disease-associated microglia (DAM) (Keren et al, 2017), we examined expression of the DAM markers Trem2, Clec7a, and CD45 within the cortex of 5XFAD/RKO compared with the 5XFAD
Our study is the first to show that the microglial phagocytosis of Aβ undergoes circadian regulation
Summary
Circadian rhythms such as the sleep–wake cycle are internal rhythms that exist on a 24-hr period. ***p < .001 compared to vehicle-treated group primary mouse microglia using siRNA targeting both REV-ERBs. We achieved a only partial knockdown of Rev-erbα (35%) and Rev-erbβ (60%) at the transcription levels, but it was adequate to induce increased expression of Bmal (Figure 4a). We examined how changes in P2Y12R expression affected microglial morphology by observing cells after SR8278 treatment in the presence or absence of fAβ1–42 This revealed that SR8278 significantly increased both microglial process length and P2Y12R expression (Figure 5b). Western blot analysis showed no differences between 5XFAD and 5XFAD/RKO in APP protein (Figure 7d), and transcript levels of Aβ-degradating enzymes including IDE, MMP2, and MMP9 showed no significant changes between the two genotype (Figure 7e), suggesting that REV-ERBα depletion did not alter APP expression and processing. Our findings indicate that REV-ERBs have important role for Aβ clearance, likely via microglia, leading to diminished plaque accumulation in REV-ERBα-deficient mice
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