Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy

Alzheimer’s disease is associated with disrupted circadian rhythms and clock gene expression. REV-ERBα (Nr1d1) is a circadian transcriptional repressor involved in the regulation of lipid metabolism and macrophage function. While global REV-ERBα deletion increases microglial activation and mitigates amyloid plaque formation, the cell-autonomous effects of microglial REV-ERBα on tau pathology are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolic processes, and causes lipid droplet (LD) accumulation specifically in male microglia. Inflammation and LD accumulation combine to inhibit microglial tau phagocytosis, which can be partially rescued by blockage of lipid droplet formation. Microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in P301S and AAV-P301L tauopathy models in male, but not female mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy. To analyze the different genes between normal mouse cultured microglia and Rev-erbα KO microglia. Control (Cre-) and REV-ERBα KO (Cre+) microglia from CAG::CreERT2; Nr1d1fl/fl P1-3 pups, treated with 4-hydroxy-tamoxifen for 2 days, and analyzed them by bulk RNA-sequencing.