Inhibiting Circadian Clock Protein Reduces Neurodegeneration

Impeding a link between the body’s natural clock and the brain may help reduce neurodegeneration in mice modeling Alzheimer’s disease, according to a new study led by researchers at WashU Medicine and published in Nature Aging.  

Erik Musiek, MD, PhD, the Charlotte & Paul Hagemann Professor of Neurology at WashU Medicine, first author Jiyeon Lee, PhD, and colleagues conducted a study on mouse models of Alzheimer’s disease and found that inhibiting the function of a key protein in the circadian system can decrease levels of a harmful protein called tau and reduce neurodegeneration. 

A circadian clock protein called REV-ERBα is known to control daily rhythms in metabolism and inflammation. Though not well studied in the brain, REV-ERBα in other tissues has been shown to regulate nicotinamide adenine dinucleotide (NAD+), which is used for cell functions such as DNA repair and metabolism. Levels of NAD+ are directly correlated to brain aging and neurodegeneration — the lower the levels, the higher the amount of brain aging. In fact, many supplements currently available on the market claim to increase NAD+ levels to decrease 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.

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: Lee J, Kang R, Park S, et al. REV-ERBα regulates brain NAD+ levels and tauopathy via an NFIL3–CD38 axis. Nat Aging. 2025:1-16. doi:10.1038/s43587-025-00950-x

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