CD38 Inhibition in Choroid Plexus Pericytes Reverses Age-Related Cognitive Decline in Mice
Blocking the NAD+-consuming enzyme CD38 in choroid plexus pericytes rejuvenates CSF and restores hippocampal memory in aged mice.
Summary
Researchers at the Buck Institute identified CD38, an NAD+-depleting enzyme, as a key driver of cognitive aging. CD38 accumulates with age primarily in choroid plexus pericytes—not in neurons—where it impairs mitochondrial function and triggers cellular senescence. Genetic deletion or pharmacological inhibition of CD38 restored NAD+ levels, rejuvenated the CSF proteome and metabolome, reversed age-related hippocampal transcriptional signatures, and improved synaptic plasticity. A novel brain-penetrant CD38 inhibitor, NTX-748, enhanced long-term potentiation and improved multiple cognitive domains in aged mice. These findings position the choroid plexus as a metabolic gatekeeper of brain aging and CD38 inhibition as a promising therapeutic target.
Detailed Summary
Age-related cognitive decline is one of the most pressing unmet challenges in medicine, yet its molecular drivers remain incompletely understood. A central thread is the progressive depletion of NAD+, a coenzyme essential to energy metabolism, DNA repair, and sirtuin activity. Prior work showed that the enzyme CD38 is the dominant NAD+-consuming enzyme in aging tissues, but its specific role in brain aging—and which brain cells express it—was unknown.
This study from the Buck Institute, led by Verdin, Fang, Ellerby, and colleagues, discovered that CD38 is expressed at dramatically elevated levels specifically in pericytes of the choroid plexus—the brain's CSF-producing structure—rather than in neurons, cortex, or hippocampus. CD38 protein and mRNA in the choroid plexus were 36.5-fold and 6.9-fold higher than in cortex and hippocampus, respectively. CD38 expression increased further between 6 and 18–24 months of age, tracking with cognitive decline.
In 18-month-old CD38 knockout (KO) mice, NAD+ metabolite pools were preserved in the choroid plexus, with elevated NMN and reduced CD38 enzymatic products (NAM and ADPR). Mitochondrial oxygen consumption—both basal and maximal—was significantly enhanced in CD38KO choroid plexus. Spatial transcriptomics (GeoMx) revealed that CD38 deficiency reversed age-related gene expression signatures in the choroid plexus, suppressing senescence-associated secretory phenotype (SASP) markers. These choroid plexus changes propagated to the CSF: proteomics and metabolomics of CSF from aged CD38KO mice showed a rejuvenated profile with reduced inflammatory signaling and enhanced neurotrophic factor content. Hippocampal transcriptomics confirmed that these CSF changes reversed age-related gene expression in the hippocampus and enhanced markers of synaptic plasticity.
Behaviorally, aged CD38KO mice outperformed wild-type controls in Barnes maze spatial learning and memory (both short- and long-term probe trials) and in a pattern separation task requiring cognitive flexibility. To translate these findings pharmacologically, the team developed NTX-748, a novel brain-penetrant CD38 inhibitor. Administered to aged mice, NTX-748 elevated NAD+ in both systemic tissues and brain, improved hippocampal long-term potentiation (LTP), and enhanced multiple cognitive domains. These effects closely mirrored those observed with genetic CD38 ablation.
Collectively, this study establishes the choroid plexus pericyte as an unexpected but critical metabolic node in brain aging and identifies a choroid plexus–CSF–hippocampus axis through which CD38 activity drives cognitive decline. The discovery of NTX-748 as a brain-penetrant inhibitor with cognitive benefits in aged animals provides a strong translational foundation for future human trials.
Key Findings
- CD38 protein in choroid plexus is 36.5-fold higher than in cortex and increases further with age.
- CD38 localizes specifically to choroid plexus pericytes, not neurons or epithelial cells.
- CD38 knockout mice show preserved NAD+ pools, enhanced mitochondrial respiration, and suppressed senescence markers in choroid plexus.
- Aged CD38KO mice outperform wild-type controls in spatial memory (Barnes maze) and pattern separation tasks.
- Brain-penetrant inhibitor NTX-748 elevates brain NAD+, improves LTP, and enhances cognition in aged mice.
Methodology
The study used 6-, 18-, and 24-month-old wild-type and CD38 knockout mice. Methods included Western blot, immunofluorescence, GeoMx spatial RNA sequencing, targeted mass spectrometry metabolomics, CSF proteomics, real-time mitochondrial respiration assays (Seahorse), hippocampal LTP electrophysiology, and behavioral cognitive testing (Barnes maze, pattern separation). Pharmacological experiments employed the novel brain-penetrant inhibitor NTX-748 in aged mice.
Study Limitations
This is a preprint and has not yet undergone formal peer review. All experiments were conducted in mice, and translation to humans requires validation. The study does not fully resolve how CSF changes mechanistically drive hippocampal transcriptional rejuvenation, and long-term safety and efficacy of NTX-748 in humans remain untested.
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