Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Endothelial NAD+ depletion drives vascular senescence and neuroinflammation via mtDNA-cGAS/STING-CD38 signaling in Alzheimer's disease.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Luo Qing-Hua, Li Fang, Yang Li, Pan Han-Qing, Zhu Wen-Ping, Hu Ping, Tao Chu-Ming, Yin Min, Zhang Si, Liao Qiu-Ye, Chen Zhi-Hao, Shu Hong-Xin, Zhu Xin-Yi, Yan Teng-Feng, Liu Xu, Tu Jiang-Long, Zhu Xin-Gen
Аннотация
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.
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.
Предметные рубрики MeSH
Alzheimer DiseaseMaleFemaleAnimalsMiceMice, TransgenicEndothelial CellsCellular SenescenceEndothelium, VascularImmunity, InnateDNA, MitochondrialCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseSTING ProteinNADCerebrovascular CirculationBlood-Brain BarrierMembrane GlycoproteinsVoltage-Dependent Anion Channel 1ADP-ribosyl Cyclase 1