Disrupting communication between the body’s internal clock and the brain could help limit neurodegeneration in Alzheimer’s disease, according to new research from Washington University School of Medicine in St. Louis (WashU Medicine). The study, published in Nature Aging, explored how changes in the circadian system affect brain health and memory in mouse models of Alzheimer’s disease.
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.