REV-ERBα regulates brain NAD+ levels and tauopathy via an NFIL3–CD38 axis
Nicotinamide adenine dinucleotide (NAD<sup>+</sup>) is a critical metabolic co-enzyme implicated in brain aging, and augmenting NAD<sup>+</sup> levels in the aging brain is an attractive therapeutic strategy for neurodegeneration. However, the molecular mechanisms of brain NAD<sup>+</sup> regulation are incompletely understood. In cardiac tissue, the circadian nuclear receptor REV-ERBα has been shown to regulate NAD<sup>+</sup> via control of the NAD<sup>+</sup>-producing enzyme NAMPT. Here we show that REV-ERBα controls brain NAD<sup>+</sup> levels through a distinct pathway involving NFIL3-dependent suppression of the NAD<sup>+</sup>-consuming enzyme CD38, particularly in astrocytes. REV-ERBα deletion does not affect NAMPT expression in the brain and has an opposite effect on NAD<sup>+</sup> levels as in the heart. Astrocytic REV-ERBα deletion augments brain NAD<sup>+</sup> and prevents tauopathy in P301S mice. Our data reveal that REV-ERBα regulates NAD<sup>+</sup> in a tissue-specific manner via opposing regulation of NAMPT versus CD38 and define an astrocyte REV-ERBα-NFIL3-CD38 pathway controlling brain NAD<sup>+</sup> metabolism and neurodegeneration.
Authors
- Thomas P. Burris (ORCID: https://orcid.org/0000-0003-2922-4449)
- Brian V. Lananna (ORCID: https://orcid.org/0000-0003-1328-9619)
- Jaymie R. Voorhees
- Ryeonghwa Kang
- Erik S. Musiek (ORCID: https://orcid.org/0000-0002-8873-0360)
- Yong Sook Goo
- Sohui Park (ORCID: https://orcid.org/0000-0003-1952-0893)
- Julie Dimitry (ORCID: https://orcid.org/0000-0002-8733-9642)
- Guoyan Zhao (ORCID: https://orcid.org/0000-0001-5615-6774)
- Lauren N. Woodie (ORCID: https://orcid.org/0000-0003-2427-4586)
- Mitchell A. Lazar (ORCID: https://orcid.org/0000-0001-8653-1280)
- Li Gan (ORCID: https://orcid.org/0000-0003-4600-275X)
- Ibrahim Olabayode Saliu (ORCID: https://orcid.org/0000-0002-6182-5992)
- Jiyeon Lee (ORCID: https://orcid.org/0000-0002-6774-2397)
- Maarten J. van Son (ORCID: https://orcid.org/0000-0001-8531-0320)
- Elsa I. Quillin
Institutions
- University of Health Sciences and Pharmacy (US)
- American Association of Colleges of Pharmacy (US)
- Washington University in St. Louis (US)
- Cornell University (US)
- University of Florida (US)
- MIND Research Institute (US)
- Weill Cornell Medicine (US)
- Ajou University (KR)
- University of Pennsylvania (US)
- Florida College (US)
Publication Details
- Journal
- Nature Aging
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1038/s43587-025-00950-x
- Citations
- 5
- Primary Topic
- Calcium signaling and nucleotide metabolism
- Type
- article
- Field-Weighted Citation Impact
- 5.59
Funders
- Cure Alzheimer's Fund
- Institute of Clinical and Translational Sciences
- Alvin J. Siteman Cancer Center
- Georgia Clinical and Translational Science Alliance
- National Research Foundation
- National Research Foundation of Korea
- Ministry of Science and ICT, South Korea
- National Institutes of Health
- National Institute on Aging
- National Cancer Institute
- National Center for Research Resources
- National Center for Advancing Translational Sciences