ASTROCYTIC REV-ERBΑ–NFIL3–CD38 AXIS GOVERNS NAD⁺ METABOLISM AND TAU PATHOLOGY

Disrupted metabolic homeostasis is a defining feature of tau-associated neurodegeneration, yet the circadian transcriptional mechanisms that regulate brain NAD⁺ metabolism remain poorly defined. REV-ERBα is a circadian transcriptional regulator that controls NAD⁺ metabolism across peripheral tissues such as the heart, but whether this regulatory framework extends to the brain has remained unclear. Here, we investigated whether circadian REV-ERBα governs brain NAD⁺ homeostasis and tau pathology through an NFIL3-dependent pathway and identified CD38 as a key downstream effector. Using genetic and pharmacological manipulation of REV-ERBα in tauopathy mouse models, we integrated bulk transcriptional, metabolic, and neuropathological analyses in vivo. Loss of REV-ERBα derepresses NFIL3, which in turn represses the NAD⁺-consuming enzyme CD38 and elevates brain NAD⁺ levels. CD38-deficient astrocytes exhibited enhanced tau uptake and phagocytic clearance, linking NAD⁺ elevation to reduced tau accumulation. These effects were accompanied by attenuation of tau pathology and were observed in both global and astrocyte-specific mouse models, demonstrating that astrocyte-specific repression of REV-ERBα is sufficient to recapitulate the global increase in brain NAD⁺ levels. Accordingly, REV-ERBα-dependent regulation of the NFIL3–CD38 pathway within astrocytes constitutes a dominant cellular mechanism, highlighting astrocytic CD38 repression as an effective strategy to enhance NAD⁺ availability and promote tau clearance. Together, our findings identify a circadian REV-ERBα–NFIL3–CD38 axis that links clock-dependent transcriptional control to brain NAD⁺ metabolism and tau pathology, and support astrocyte-targeted modulation of CD38 as a rational approach to counter metabolic vulnerability in tau-associated neurodegeneration.