Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Neurosurgery, Medical School, University of Pecs, Hungary.
Redox Biol. 2019 Jun;24:101192. doi: 10.1016/j.redox.2019.101192. Epub 2019 Apr 10.
Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In aging increased oxidative stress and cerebromicrovascular endothelial dysfunction impair NVC, contributing to cognitive decline. There is increasing evidence showing that a decrease in NAD availability with age plays a critical role in a range of age-related cellular impairments but its role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that restoring NAD concentration may exert beneficial effects on NVC responses in aging. To test this hypothesis 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD intermediate, for 2 weeks. NVC was assessed by measuring CBF responses (laser Doppler flowmetry) evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. NMN supplementation rescued NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory and gait coordination. These findings are paralleled by the sirtuin-dependent protective effects of NMN on mitochondrial production of reactive oxygen species and mitochondrial bioenergetics in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, a decrease in NAD availability contributes to age-related cerebromicrovascular dysfunction, exacerbating cognitive decline. The cerebromicrovascular protective effects of NMN highlight the preventive and therapeutic potential of NAD intermediates as effective interventions in patients at risk for vascular cognitive impairment (VCI).
通过神经血管耦合（NVC）来调节脑血流（CBF）以适应神经元活动，在维持健康的认知功能方面起着至关重要的作用。在衰老过程中，氧化应激增加和脑微血管内皮功能障碍会损害 NVC，导致认知能力下降。越来越多的证据表明，随着年龄的增长，NAD 可用性的降低在一系列与年龄相关的细胞损伤中起着关键作用，但它在受损的 NVC 反应中的作用仍未得到探索。本研究旨在测试以下假设，即恢复 NAD 浓度可能对衰老过程中的 NVC 反应产生有益影响。为了验证这一假设，用烟酰胺单核苷酸（NMN），一种关键的 NAD 中间体，对 24 个月大的 C57BL/6 小鼠进行了为期 2 周的治疗。通过测量对侧胡须刺激引起的 CBF 反应（激光多普勒血流测量）来评估 NVC。结果发现，NVC 反应在老年小鼠中明显受损。NMN 补充通过增加内皮一氧化氮介导的血管舒张来挽救 NVC 反应，这与空间工作记忆和步态协调能力的显著改善有关。这些发现与 NMN 对培养的来自老年动物的脑微血管内皮细胞中线粒体产生的活性氧物质和线粒体生物能量学的 Sirtuin 依赖性保护作用相平行。因此，NAD 可用性的降低导致与年龄相关的脑微血管功能障碍，加剧认知能力下降。NMN 对脑微血管的保护作用突出了 NAD 中间体作为血管性认知障碍（VCI）高危患者的有效干预措施的预防和治疗潜力。
