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.