REV-ERBα regulates brain NAD+ levels and tauopathy via an NFIL3–CD38 axis

Nicotinamide adenine dinucleotide (NAD+) is a critical metabolic co-enzyme implicated in brain aging, and augmenting NAD+ levels in the aging brain is an attractive therapeutic strategy for neurodegeneration. However, the molecular mechanisms of brain NAD+ regulation are incompletely understood. In cardiac tissue, the circadian nuclear receptor REV-ERBα has been shown to regulate NAD+ via control of the NAD+-producing enzyme NAMPT. Here we show that REV-ERBα controls brain NAD+ levels through a distinct pathway involving NFIL3-dependent suppression of the NAD+-consuming enzyme CD38, particularly in astrocytes. REV-ERBα deletion does not affect NAMPT expression in the brain and has an opposite effect on NAD+ levels as in the heart. Astrocytic REV-ERBα deletion augments brain NAD+ and prevents tauopathy in P301S mice. Our data reveal that REV-ERBα regulates NAD+ in a tissue-specific manner via opposing regulation of NAMPT versus CD38 and define an astrocyte REV-ERBα–NFIL3–CD38 pathway controlling brain NAD+ metabolism and neurodegeneration. Lee et al. show that the circadian clock protein REV-ERBα controls brain NAD+ levels by regulating the NAD+-consuming enzyme CD38. Global or astrocytic REV-ERBα deletion or pharmacologic REV-ERB inhibition protects against tau pathology in mice.