Researchers at Washington University discovered that the circadian clock protein REV-ERBα regulates brain NAD+ levels through a pathway distinct from other tissues. In the brain—particularly in astrocytes—REV-ERBα suppresses NFIL3, which in turn normally keeps the NAD+-consuming enzyme CD38 in check. Deleting REV-ERBα globally or specifically in astrocytes de-represses NFIL3, suppresses CD38, and raises brain NAD+ levels. Strikingly, this also reduces tau pathology in P301S tauopathy mice. Pharmacological inhibition of REV-ERBα similarly protected against tau accumulation. The findings highlight tissue-specific NAD+ regulation and suggest REV-ERBα inhibitors as a potential strategy against Alzheimer's disease and related tauopathies.
