HMN 2025: How Circadian clock protein is linked to brain aging and neurodegenerative disease

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, Ph.D., the Charlotte & Paul Hagemann Professor of Neurology at WashU Medicine, first author Jiyeon Lee, Ph.D., 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-ERB? is known to control daily rhythms in metabolism and inflammation. Though not well studied in the brain, REV-ERB? 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-ERB? 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-ERB? 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-ERB?, both genetically and with a novel drug that has shown promise in amyloid-? 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.

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