Endothelial NADdepletion drives vascular senescence and neuroinflammation via mtDNA-cGAS/STING-CD38 signaling in Alzheimer's disease.

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 NADhomeostasis mitigates AD-related vascular and inflammatory pathology. RESULTS: NADdeficiency 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 NADdeficiency 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 NADrestoration as a promising AD therapeutic strategy.