Disabling a clock protein shields the brain from Alzheimer’s effects—hinting at a new path for neuroprotection.
Disrupting the connection between the body’s internal clock and the brain may slow the progression of neurodegeneration in mice with Alzheimer’s-like symptoms, according to new research from Washington University School of Medicine published in Nature Aging.
Erik Musiek, MD, PhD, the Charlotte & Paul Hagemann Professor of Neurology at WashU Medicine, along with first author Jiyeon Lee, PhD, and their team, investigated how suppressing the activity of a major circadian protein affects brain health. In mouse models of Alzheimer’s disease, they found that blocking this protein’s function lowered the accumulation of a toxic protein known as tau and reduced neurodegeneration.
How the circadian protein influences brain aging
The circadian protein REV-ERBα helps regulate daily cycles of metabolism and inflammation. While its role in the brain has not been thoroughly explored, studies in other tissues indicate that it influences levels of nicotinamide adenine dinucleotide (NAD+), a molecule essential for energy metabolism and DNA repair. NAD+ levels are closely tied to brain aging and neurodegeneration — lower concentrations are linked with faster neural decline. Many over-the-counter supplements on the market today claim to boost NAD+ levels as a way to counteract aging.
Musiek and his team genetically deleted REV-ERBα throughout all tissues in one group of mice, and, in a separate group of mice, they deleted the protein only in astrocytes — glial cells that make up much of the central nervous system. NAD+ levels increased in both instances. This provided evidence that REV-ERBα deletion in astrocytes has a direct impact on the levels of NAD+ in the brain, providing a pathway for potential neurodegenerative treatment studies in the future.
Drug inhibition and neuroprotection in Alzheimer’s models
The researchers also discovered that inhibiting REV-ERBα, both genetically and with a novel drug that has shown promise in amyloid-β pathology and Parkinson disease studies, led to higher levels of NAD+ and protected the mice from tau pathology, the toxic aggregation of proteins in the brain that lead to neurodegenerative diseases.
The results from the experimental drug may reveal a new therapeutic approach to preventing and treating Alzheimer’s disease.
Reference: “REV-ERBα regulates brain NAD+ levels and tauopathy via an NFIL3–CD38 axis” by Jiyeon Lee, Ryeonghwa Kang, Sohui Park, Ibrahim O. Saliu, Minsoo Son, Jaymie R. Voorhees, Julie M. Dimitry, Elsa I. Quillin, Lauren N. Woodie, Brian V. Lananna, Li Gan, Young-Ah Goo, Guoyan Zhao, Mitchell A. Lazar, Thomas P. Burris and Erik S. Musiek, 01 September 2025, Nature Aging.
DOI: 10.1038/s43587-025-00950-x
This study was supported by the following grants: National Institute on Aging R01AG063743 (E.S.M.) and RF1AG061776 (E.S.M.); Cure Alzheimer’s Fund Research Grant (E.S.M.); McDonnell Center for Cellular and Molecular Neurobiology Postdoctoral Fellowship (J.L.); National Research Foundation of Korea RS-2019-NR040055, funded by the Korean Ministry of Science and ICT (J.L); and National Institutes of Health (NIH) RF1AG062077 (M.L.), R35NS097273 (M.L.), RF1AG062171 (M.L.), P01NS084974-01 (M.L.) and R01DK45586 (M.L.).
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