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.