| First Author | Zhan R | Year | 2023 |
| Journal | Neuron | Volume | 111 |
| Issue | 22 | Pages | 3634-3649.e7 |
| PubMed ID | 37683629 | Mgi Jnum | J:342619 |
| Mgi Id | MGI:7550297 | Doi | 10.1016/j.neuron.2023.08.010 |
| Citation | Zhan R, et al. (2023) NAD(+) rescues aging-induced blood-brain barrier damage via the CX43-PARP1 axis. Neuron 111(22):3634-3649.e7 |
| abstractText | 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. |
