Body Clock Protein Found to Protect the Brain by Boosting Vital Energy Molecule

A new study has uncovered a surprising, brain-specific mechanism through which the circadian protein REV-ERBα regulates levels of the key metabolic cofactor NAD+, revealing a potential new therapeutic target for Alzheimer’s disease (AD) and related neurodegenerative disorders.

Researchers report that REV-ERBα suppresses brain NAD+ levels by promoting expression of the NAD+-consuming enzyme CD38, a mechanism distinct from its previously described role in the heart. In the brain, deleting or inhibiting REV-ERBα increased NAD+ concentrations, improved astrocyte function, and reduced tau accumulation and neurodegeneration in mouse models of tauopathy.

The findings, published this week in Nature Neuroscience, redefine how NAD+ metabolism is regulated in the central nervous system and highlight the therapeutic potential of REV-ERBα inhibitors and CD38 blockers for neurodegenerative diseases.

Nicotinamide adenine dinucleotide (NAD+) is an essential metabolic cofactor involved in redox balance, DNA repair, and sirtuin-dependent protein deacetylation. Declining NAD+ levels are a hallmark of aging and have been linked to neurodegeneration. While boosting NAD+ has been proposed as a neuroprotective strategy, the molecular control of NAD+ in the brain has remained unclear.

REV-ERBα, a nuclear receptor that integrates circadian rhythms with metabolic and inflammatory pathways, was already known to regulate NAD+ in the heart by controlling NAMPT, the rate-limiting enzyme in NAD+ synthesis. In this new work, however, the authors demonstrate that brain REV-ERBα does not affect NAMPT. Instead, it operates through a distinct astrocyte-specific mechanism, repressing the transcription factor NFIL3, which in turn suppresses CD38, the enzyme responsible for NAD+ consumption.

Deletion of REV-ERBα, either globally or specifically in astrocytes, increased NAD+ levels in the brain and protected against tau pathology in P301S tauopathy mice, a model of Alzheimer’s disease. Pharmacological inhibition of REV-ERBα with the antagonist SR8278 produced similar neuroprotective effects.

Mechanistic studies revealed that elevated NAD+ in astrocytes enhanced lysosomal activity and tau uptake, promoting clearance of toxic tau aggregates. This astrocyte-driven protection occurred without detectable neuroinflammation, suggesting that targeted modulation of REV-ERBα can support protein homeostasis in the aging brain.

The data also contrast with previous findings that microglia-specific REV-ERBα deletion worsens tau pathology in male mice, highlighting cell-type- and tissue-specific roles for this nuclear receptor. Overall, the balance of effects, particularly in astrocytes, appears protective when REV-ERBα activity is inhibited.

The discovery of a REV-ERBα–NFIL3–CD38 axis that governs NAD+ metabolism in the brain opens multiple translational avenues.

• REV-ERBα antagonists may provide a means to boost brain NAD+ and mitigate tau accumulation.

• CD38 inhibitors, already under investigation for metabolic and inflammatory disorders, could gain traction as candidates for neurodegenerative disease modification.

• The work underscores the importance of cell-type-selective targeting in drug development for circadian and metabolic regulators.

The researchers note that while total genetic deletion of REV-ERBα can have deleterious effects during development, partial pharmacological inhibition in adulthood appears to enhance neuroprotection without adverse inflammation. This nuance could guide the design of small-molecule modulators optimized for CNS indications.

REV-ERBα’s role in linking circadian regulation, metabolism, and proteostasis positions it as a key node in the biology of aging and neurodegeneration. As lead author notes, “Our results reveal that REV-ERBα functions very differently across tissues, suppressing NAD+ production in the heart, but restraining NAD+ consumption in the brain. Understanding these tissue-specific mechanisms is essential for translating circadian biology into safe, effective therapeutics.”

Given the ongoing industrial interest in NAD+ augmentation, circadian modulation, and glial biology, this study provides both mechanistic clarity and new targets for drug discovery programs aimed at Alzheimer’s disease, tauopathies, and age-related brain decline.