Clock Protein REV-ERBα Controls Brain NAD+ via Astrocyte CD38 Pathway
Blocking the circadian protein REV-ERBα boosts brain NAD+ and protects against tau pathology in mice, revealing a new therapeutic target.
Summary
Researchers at Washington University discovered that the circadian clock protein REV-ERBα regulates brain NAD+ levels through a pathway distinct from other tissues. In the brain—particularly in astrocytes—REV-ERBα suppresses NFIL3, which in turn normally keeps the NAD+-consuming enzyme CD38 in check. Deleting REV-ERBα globally or specifically in astrocytes de-represses NFIL3, suppresses CD38, and raises brain NAD+ levels. Strikingly, this also reduces tau pathology in P301S tauopathy mice. Pharmacological inhibition of REV-ERBα similarly protected against tau accumulation. The findings highlight tissue-specific NAD+ regulation and suggest REV-ERBα inhibitors as a potential strategy against Alzheimer's disease and related tauopathies.
Detailed Summary
NAD+ is a vital coenzyme that declines with age in the brain, and restoring its levels is a promising strategy against neurodegeneration. The circadian nuclear receptor REV-ERBα was already known to regulate NAD+ in the heart by controlling the NAD+-producing enzyme NAMPT. This study asked whether a similar mechanism operates in the brain and whether it influences tau-driven neurodegeneration.
Using inducible global REV-ERBα knockout (RKO) mice and astrocyte-specific knockouts, the team performed bulk RNA-sequencing of hippocampal tissue and measured NAD+ concentrations across brain regions. Contrary to findings in cardiac tissue, REV-ERBα deletion in the brain did not affect NAMPT expression. Instead, deletion increased expression of the transcription factor NFIL3 (a known REV-ERB target) and dramatically suppressed CD38, the primary NAD+-consuming enzyme in the brain. The net result was a significant increase in brain NAD+ levels—an effect opposite to what REV-ERBα deletion produces in the heart, demonstrating clear tissue-specificity.
Cell-type dissection revealed that astrocytes are the primary locus of this pathway. Astrocyte-specific REV-ERBα deletion recapitulated the increase in brain NAD+ seen in global knockouts. Mechanistically, REV-ERBα represses NFIL3, which in turn activates CD38 transcription; loss of REV-ERBα therefore de-represses NFIL3, which then suppresses CD38, elevating NAD+. siRNA knockdown of NFIL3 in primary astrocytes increased CD38 expression, confirming the regulatory axis.
Critically, both global and astrocyte-specific REV-ERBα deletion significantly attenuated tau pathology in P301S (PS19) tauopathy mice, a well-validated model of Alzheimer's-related neurodegeneration. Pharmacological antagonism of REV-ERBα with a small-molecule inhibitor also reduced tau burden, suggesting therapeutic tractability. The protection correlated with elevated NAD+ and improved sirtuin-dependent deacetylase activity, consistent with NAD+-mediated neuroprotection.
These findings reframe REV-ERBα as a brain-specific NAD+ regulator acting through CD38 suppression in astrocytes rather than NAMPT regulation, and position the REV-ERBα–NFIL3–CD38 axis as a novel therapeutic target for Alzheimer's disease and related tauopathies. Caution is warranted given prior data showing microglia-specific REV-ERBα deletion can worsen tau pathology in male mice, underscoring the importance of cell-type specificity in any therapeutic approach.
Key Findings
- REV-ERBα deletion raises brain NAD+ by suppressing CD38, not NAMPT—opposite to its cardiac mechanism.
- An astrocyte REV-ERBα–NFIL3–CD38 axis is the primary pathway controlling brain NAD+ metabolism.
- Global or astrocyte-specific REV-ERBα deletion significantly reduces tau pathology in P301S mice.
- Pharmacological REV-ERBα antagonism also mitigates tau burden, suggesting drug-targetable therapeutic potential.
- REV-ERBα regulates NAD+ in a tissue-specific manner, with opposing effects in brain versus heart.
Methodology
Study used inducible global and astrocyte-specific REV-ERBα knockout mice, bulk hippocampal RNA-seq, NAD+ quantification across timepoints, primary astrocyte siRNA experiments, and the P301S tau mouse model with both genetic and pharmacological REV-ERBα inhibition.
Study Limitations
All in vivo data are from mouse models; human translation is unconfirmed. Microglia-specific REV-ERBα deletion was previously shown to worsen tau pathology in males, indicating complex cell-type interactions that complicate systemic dosing strategies. Long-term safety of sustained REV-ERBα inhibition across tissues remains unknown.
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