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

Nicotinamide adenine dinucleotide (NAD+) is a critical metabolic co-enzyme which is strongly implicated in the pathogenesis of brain aging and neurodegenerative diseases. Prevention of age-related decline in brain NAD+ levels is an attractive therapeutic strategy for combating age-related neurodegeneration, emphasizing the need to fully understand molecular mechanisms regulating brain NAD+ levels. Previous work has shown that the circadian protein REV-ERBa regulates cellular NAD+ levels in cardiac tissue via control of the NAD+ producing enzyme NAMPT. Whether this pathway regulates brain NAD+ levels, however, is unknown. Here, we show that REV-ERBa controls brain NAD+ levels through a distinct pathway involving suppression of the NAD+ consuming enzyme CD38 in astrocytes. Under basal conditions, REV-ERBa suppresses the transcription factor NFIL3 (E4BP4) which itself provides tonic inhibition of CD38 expression, elevating CD38 levels and keeping NAD+ levels low. Deletion of REV-ERBa, either globally or specifically in astrocytes, led to induction of NFIL3, suppression of CD38, increased NAD+, and mitigated protein aggregation, inflammation, and neurodegeneration in a mouse model of tauopathy. This pathway appears to be unique to the brain, as REV-ERBa deletion does not affect NAMPT expression in the brain, does not suppress CD38 in the liver, and has an opposite effect on NAD+ levels in the brain as in the heart. Our data show that the circadian nuclear receptor REV-ERBa can regulate NAD+ via distinct mechanisms in different tissues and define a REV-ERBa-NFIL3-NAD+ downstream pathway controlling brain NAD+ metabolism and neurodegeneration. Overall design: To analyze the differentially expressed genes among four groups including WT, RKO, PS19, and PS19;RKO, mouse hippocampus RNA samples from each groups were prepared and anlyzed by bulk RNA-sequencing.