Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy
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ABSTRACT: 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 deletion in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deficient enhances inflammatory signaling, disrupts lipid metabolism, 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.
INSTRUMENT(S): Orbitrap Exploris 480
ORGANISM(S): Mus Musculus (mouse)
TISSUE(S): Brain, Microglial Cell
DISEASE(S): Alzheimer's Disease
SUBMITTER: Minsoo Son
LAB HEAD: Erik Musiek
PROVIDER: PXD043877 | Pride | 2023-08-09
REPOSITORIES: Pride
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