NAD+ rescues aging-induced blood-brain barrier damage via the CX43-PARP1 axis

Neuron. 2023 Nov 15;111(22):3634-3649.e7. doi: 10.1016/j.neuron.2023.08.010. Epub 2023 Sep 7.


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.

Keywords: BBB; CX43; NAD(+); PARP1; aging; long-term NMN administration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology
  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain / metabolism
  • Connexin 43* / genetics
  • Connexin 43* / metabolism
  • Humans
  • Mice
  • NAD* / metabolism
  • Poly (ADP-Ribose) Polymerase-1 / metabolism


  • Connexin 43
  • NAD
  • PARP1 protein, human
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • GJA1 protein, mouse