CD38 Inhibition Ameliorates Age-Related Cognitive Decline via a Choroid Plexus–Cerebrospinal Fluid–Hippocampus Axis
Year: 2026
Type: preprint
Abstract: Age-related cognitive decline represents a major and unresolved challenge of human aging. Here, we identify the NAD⁺-consuming enzyme CD38 as a central regulator of cognitive aging acting through a choroid plexus–cerebrospinal fluid (CSF)–hippocampus axis. CD38 expression increases with age and localizes primarily to pericytes in the choroid plexus, where it depletes NAD⁺, impairs mitochondrial function, and promotes cellular senescence. Genetic ablation or pharmacological inhibition of CD38 restores NAD⁺ levels, suppresses senescence markers, and improves choroid plexus function, resulting in a rejuvenated CSF proteomic and metabolomic profile characterized by reduced inflammatory signaling and enhanced neurotrophic support. These changes propagate to the hippocampus, reversing age-related transcriptional signatures and enhancing synaptic plasticity. A novel, brain-penetrant CD38 inhibitor, NTX-748, reproduced the benefits of CD38 deficiency—elevating systemic and brain NAD⁺ levels, improving long-term potentiation, and enhancing multiple domains of cognition in aged mice. Collectively, these findings identify the choroid plexus as a metabolic gatekeeper of brain aging and establish CD38 inhibition as a promising therapeutic strategy to promote cognitive resilience and healthy brain aging.
Source: Research Square
Authors: Eric Verdin, Jingqi Fang, Rebeccah Riley, Kevin Schneider, Rosalba Perrone, Prasanna Kumaar, Christina King, Grant Kauwe, Andrea Roberts, Genesis Vega Hormazabal, Yini Zhang, Ethan Millard, Xinran Liu, Wendy Jara, Carlos Galicia Aguirre, Harrison Baker, Natalia Murad, Ben Ambrose, Tommy Tran, Nicolas Martin, Ran Zhang, Durai Sellegounder, Simon Melov, David Furman, Tara Tracy, Akos Gerencser, Birgit Schilling, Lisa Ellerby
Institution: Buck Institute for Research on Aging
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7118708510