Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice
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 transcri...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40927-1 |
| _version_ | 1797414691168845824 |
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| author | Jiyeon Lee Julie M. Dimitry Jong Hee Song Minsoo Son Patrick W. Sheehan Melvin W. King G. Travis Tabor Young Ah Goo Mitchell A. Lazar Leonard Petrucelli Erik S. Musiek |
| author_facet | Jiyeon Lee Julie M. Dimitry Jong Hee Song Minsoo Son Patrick W. Sheehan Melvin W. King G. Travis Tabor Young Ah Goo Mitchell A. Lazar Leonard Petrucelli Erik S. Musiek |
| author_sort | Jiyeon Lee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T05:37:13Z |
| format | Article |
| id | doaj.art-e11bb6f0f9374829a3ba4ffb52959f1b |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T05:37:13Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-e11bb6f0f9374829a3ba4ffb52959f1b2023-12-03T12:28:33ZengNature PortfolioNature Communications2041-17232023-08-0114111710.1038/s41467-023-40927-1Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male miceJiyeon Lee0Julie M. Dimitry1Jong Hee Song2Minsoo Son3Patrick W. Sheehan4Melvin W. King5G. Travis Tabor6Young Ah Goo7Mitchell A. Lazar8Leonard Petrucelli9Erik S. Musiek10Department of Neurology and Center On Biological Rhythms And Sleep, Washington University School of MedicineDepartment of Neurology and Center On Biological Rhythms And Sleep, Washington University School of MedicineMass Spectrometry Technology Access Center at McDonnell Genome Institute (MTAC@MGI) at Washington University School of MedicineMass Spectrometry Technology Access Center at McDonnell Genome Institute (MTAC@MGI) at Washington University School of MedicineDepartment of Neurology and Center On Biological Rhythms And Sleep, Washington University School of MedicineDepartment of Neurology and Center On Biological Rhythms And Sleep, Washington University School of MedicineDepartment of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of MedicineMass Spectrometry Technology Access Center at McDonnell Genome Institute (MTAC@MGI) at Washington University School of MedicineInstitute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of PennsylvaniaDepartment of Neuroscience, Mayo ClinicDepartment of Neurology and Center On Biological Rhythms And Sleep, Washington University School of MedicineAbstract 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.https://doi.org/10.1038/s41467-023-40927-1 |
| spellingShingle | Jiyeon Lee Julie M. Dimitry Jong Hee Song Minsoo Son Patrick W. Sheehan Melvin W. King G. Travis Tabor Young Ah Goo Mitchell A. Lazar Leonard Petrucelli Erik S. Musiek Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice Nature Communications |
| title | Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice |
| title_full | Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice |
| title_fullStr | Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice |
| title_full_unstemmed | Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice |
| title_short | Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice |
| title_sort | microglial rev erbα regulates inflammation and lipid droplet formation to drive tauopathy in male mice |
| url | https://doi.org/10.1038/s41467-023-40927-1 |
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