| First Author | Lee J | Year | 2023 |
| Journal | Nat Commun | Volume | 14 |
| Issue | 1 | Pages | 5197 |
| PubMed ID | 37626048 | Mgi Jnum | J:339653 |
| Mgi Id | MGI:7523669 | Doi | 10.1038/s41467-023-40927-1 |
| Citation | Lee J, et al. (2023) Microglial REV-ERBalpha regulates inflammation and lipid droplet formation to drive tauopathy in male mice. Nat Commun 14(1):5197 |
| abstractText | Alzheimer's disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBalpha is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBalpha deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBalpha in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBalpha deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. These events impair microglial tau phagocytosis, which can be partially rescued by blockage of LD formation. In vivo, microglial REV-ERBalpha deletion exacerbates tau aggregation and neuroinflammation in two mouse tauopathy models, specifically in male mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBalpha as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy. |
