NAD+ rescues aging-induced blood-brain barrier damage via the CX43-PARP1 axis.
Neuron
; 111(22): 3634-3649.e7, 2023 11 15.
Article
en En
| MEDLINE
| ID: mdl-37683629
ABSTRACT
Blood-brain barrier (BBB) function deteriorates during aging, contributing to cognitive impairment and neurodegeneration. It is unclear what drives BBB leakage in aging and how it can be prevented. Using single-nucleus transcriptomics, we identified decreased connexin 43 (CX43) expression in cadherin-5+ (Cdh5+) cerebral vascular cells in naturally aging mice and confirmed it in human brain samples. Global or Cdh5+ cell-specific CX43 deletion in mice exacerbated BBB dysfunction during aging. The CX43-dependent effect was not due to its canonical gap junction function but was associated with reduced NAD+ levels and mitochondrial dysfunction through NAD+-dependent sirtuin 3 (SIRT3). CX43 interacts with and negatively regulates poly(ADP-ribose) polymerase 1 (PARP1). Pharmacologic inhibition of PARP1 by olaparib or nicotinamide mononucleotide (NMN) supplementation rescued NAD+ levels and alleviated aging-associated BBB leakage. These findings establish the endothelial CX43-PARP1-NAD+ pathway's role in vascular aging and identify a potential therapeutic strategy to combat aging-associated BBB leakage with neuroprotective implications.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Conexina 43
/
NAD
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Neuron
Asunto de la revista:
NEUROLOGIA
Año:
2023
Tipo del documento:
Article