Endothelial NAD+ depletion drives vascular senescence and neuroinflammation via mtDNA-cGAS/STING-CD38 signaling in Alzheimer's disease

  • Alzheimers Dement. 2026 Apr;22(4):e71423. doi: 10.1002/alz.71423.
Qing-Hua Luo  1  2 ,  Fang Li  1 ,  Li Yang  2  3 ,  Han-Qing Pan  1 ,  Wen-Ping Zhu  2  3 ,  Ping Hu  2  3 ,  Chu-Ming Tao  1  2 ,  Min Yin  1 ,  Si Zhang  2  3 ,  Qiu-Ye Liao  2  3 ,  Zhi-Hao Chen  2  3 ,  Hong-Xin Shu  2  3 ,  Xin-Yi Zhu  2  3 ,  Teng-Feng Yan  2  3 ,  Xu Liu  1 ,  Jiang-Long Tu  1  2 ,  Xin-Gen Zhu  2  3
Affiliations
  • 1. Department of Neurology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, P. R. China.
  • 2. Jiangxi Clinical Medical Research Center of Nervous System Diseases, Nanchang, Jiangxi, P. R. China.
  • 3. Department of Neurosurgery, Jiangxi Province Key Laboratory of Neurological Diseases, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, P. R. China.
PMID: 42033099 DOI: 10.1002/alz.71423
Abstract

Background: Endothelial dysfunction has emerged as early and pivotal event in Alzheimer's disease (AD), yet the molecular mechanisms linking vascular aging to neuroinflammation remain elusive.

Methods: We used APP/PS1 mice and amyloid beta (Aβ)-challenged brain endothelial cells (BECs) to understand the mechanisms of nicotinamide adenine dinucleotide (NAD+) deficiency, and its relationship with endothelial senescence and neuroinflammation in AD pathology. Nicotinamide riboside supplementation was administered to APP/PS1 mice to determine whether restoration of NAD+ homeostasis mitigates AD-related vascular and inflammatory pathology.

Results: NAD+ deficiency induced voltage-dependent anion channel 1 (VDAC1) oligomerization, mitochondrial DNA (mtDNA) leakage, and cGAS/STING-IRF3 activation, promoting endothelial senescence and SASP production with NAD+-consuming enzyme CD38 upregulation. Senescent BECs triggered IL-6-dependent microglial activation. NR treatment restored mitochondrial integrity, suppressed cGAS-STING signaling, and reduced neuroinflammation, improving vascular function and cognition.

Discussion: Aβ-driven NAD+ deficiency initiates a VDAC1-mtDNA-cGAS/STING cascade that promotes endothelial senescence and neurovascular inflammation in AD pathology, and amplifies neuroinflammation through BEC-microglia crosstalk, highlighting NAD+ restoration as a promising AD therapeutic strategy.

Keywords
Alzheimer's disease; NAD+ supplementation; cGAS/STING pathway; endothelial senescence; neuroinflammation.
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