한빛사논문
- 조회1,076
Jiyeon Lee 1, Julie M. Dimitry 1, Jong Hee Song 2, Minsoo Son 2, Patrick W. Sheehan 1, Melvin W. King 1, G. Travis Tabor 3, Young Ah Goo 2, Mitchell A. Lazar 4, Leonard Petrucelli 5 & Erik S. Musiek 1,*
1Department of Neurology and Center On Biological Rhythms And Sleep, Washington University School of Medicine, St. Louis, MO, USA.
2Mass Spectrometry Technology Access Center at McDonnell Genome Institute (MTAC@MGI) at Washington University School of Medicine, St. Louis, MO, USA.
3Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
4Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
5Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
*Corresponding author: correspondence to Erik S. Musiek
Abstract
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-ERBα 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-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBα in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα 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-ERBα 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-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.
논문정보
- Research article
- 2023년 08월 (BRIC 등록일 2023-09-04)
- 국외 연구진
- 생명과학 > 신경생물학
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