NAD+ Depletion in Brain Blood Vessels Sparks Alzheimer's Neuroinflammation

Alzheimer's disease (AD) has long been framed around amyloid plaques and tau tangles, but cerebrovascular dysfunction is increasingly recognized as an early driver of neurodegeneration. This study, published in Alzheimer's & Dementia, pinpoints a previously underappreciated molecular cascade linking endothelial NAD+ depletion to neuroinflammation in AD.

Using APP/PS1 transgenic mice and Aβ-challenged brain endothelial cells (BECs), the researchers showed that amyloid beta—particularly Aβ1-40, which accumulates along cerebral vessels—induces a marked drop in intracellular NAD+ levels. This metabolic deficit destabilizes the mitochondrial outer membrane protein VDAC1, causing it to oligomerize and form pores through which mitochondrial DNA (mtDNA) leaks into the cytosol. Cytosolic mtDNA acts as a damage-associated molecular pattern (DAMP) that activates cGAS, which synthesizes cGAMP to engage STING and downstream IRF3/NF-κB signaling. The result is a robust senescence-associated secretory phenotype (SASP) in BECs, accompanied by upregulation of CD38—an NAD+-consuming ectoenzyme—creating a vicious cycle of further NAD+ depletion.

Senescent BECs were shown to actively propagate neuroinflammation through paracrine IL-6 signaling. Secreted IL-6 activated the IL-6R/STAT3/NF-κB axis in adjacent microglia, promoting their perivascular clustering and sustained inflammatory activation. This endothelial–microglial crosstalk amplified neurovascular pathology beyond the vessel wall itself.

To test therapeutic reversibility, the team administered nicotinamide riboside (NR)—a bioavailable NAD+ precursor—to APP/PS1 mice via drinking water from 3 to 6 months of age. RNA sequencing of vessel-enriched brain fractions confirmed that NR treatment broadly reversed the transcriptomic signature of vascular senescence and inflammation. Mechanistically, NR restored mitochondrial membrane integrity, suppressed VDAC1 oligomerization and mtDNA leakage, silenced cGAS/STING-IRF3 signaling, reduced CD38 expression, and disrupted the maladaptive endothelial–microglial crosstalk. Behaviorally, NR-treated AD mice showed improved cognitive performance alongside enhanced vascular function.

These findings reframe endothelial senescence as a mechanistically active, targetable node in AD pathogenesis. The identification of the VDAC1–mtDNA–cGAS/STING–CD38 axis as a feedforward loop that simultaneously drives senescence and depletes the metabolite needed to prevent it provides a compelling rationale for early vascular NAD+ intervention in AD.