Led by Erik Musiek, MD, PhD, the Charlotte & Paul Hagemann Professor of Neurology at WashU Medicine, and first author Jiyeon Lee, PhD, the research team investigated whether blocking a specific circadian clock protein might slow the progression of neurodegeneration. They found that inhibiting the activity of this protein lowered levels of tau, a toxic protein linked to Alzheimer's pathology, and reduced damage to brain tissue.

REV-ERBα, NAD⁺, and Brain Aging

The circadian protein under investigation, called REV-ERBα, helps regulate the body's daily rhythms of metabolism and inflammation. While its role in the brain has been less understood, earlier studies in other tissues showed that REV-ERBα influences levels of nicotinamide adenine dinucleotide (NAD⁺), a molecule vital for metabolism, energy production, and DNA repair. Declining NAD⁺ levels are closely associated with brain aging and neurodegenerative conditions. Many over-the-counter supplements aim to raise NAD⁺ as a strategy to slow aging and promote cellular health.

To test REV-ERBα's role, the team genetically deleted the protein in two groups of mice: one in which the deletion occurred throughout the body, and another where it was removed only in astrocytes (supportive glial cells that form a major part of the central nervous system). In both cases, NAD⁺ levels rose significantly. The results suggest that eliminating REV-ERBα in astrocytes directly boosts NAD⁺ in the brain, pointing to a potential path for future treatments targeting neurodegeneration.

Drug Treatment Protects Against Tau Pathology

In a further experiment, the researchers blocked REV-ERBα using both genetic methods and a new drug that has also shown promise in studies of amyloid-β and Parkinson's disease. This approach increased NAD⁺ levels and shielded the mice from tau-related brain damage. Tau aggregates are known to disrupt brain function and drive neurodegenerative diseases such as Alzheimer's.

The findings suggest that manipulating the body's internal clock -- specifically by inhibiting REV-ERBα -- could represent a new way to protect the brain, prevent tau buildup, and potentially slow or halt the progression of Alzheimer's disease.