Washington University scientists report that inhibiting the circadian regulator REV-ERBα raised brain NAD+ and reduced tau pathology in mouse models, pointing to a clock-focused strategy worth exploring for Alzheimer’s disease.
A study from Washington University School of Medicine in St. Louis finds that dialing down the circadian regulator REV-ERBα raises brain levels of nicotinamide adenine dinucleotide (NAD+) and reduces tau pathology in mice. The work, led by Erik S. Musiek, MD, PhD, with first author Jiyeon Lee, PhD, appears in Nature Aging (volume 5, pages 2070–2085), published online September 1, 2025 and included in the journal’s October 2025 issue. (nature.com)
In the experiments, deleting REV-ERBα globally—and separately only in astrocytes—elevated brain NAD+ and blunted tau-related injury in PS19 (P301S) mice, pointing to astrocytes as a key control point. The authors report that REV-ERBα influences brain NAD+ through an NFIL3–CD38 pathway; astrocyte-specific deletion increased NAD+ without altering NAMPT expression. (nature.com)
Beyond genetics, the team tested a small‑molecule antagonist of REV‑ERBα (SR8278) and found initial evidence it could also lessen tau pathology in mice. Prior work has linked REV‑ERB inhibition—including SR8278—to enhanced amyloid‑β clearance in microglia, and a separate study in a Parkinson’s disease mouse model reported time‑of‑day–dependent improvements in mood‑related behaviors with SR8278. (nature.com)
Taken together, the results underscore a connection between the brain’s clock, NAD+ metabolism, and neurodegeneration, while highlighting a potential therapeutic angle that will require validation in people. Musiek is the Charlotte & Paul Hagemann Professor of Neurology at Washington University; Lee is the paper’s first author. (source.washu.edu)
