Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, Texas.
Department of Kinesiology and Cardiovascular Research Center, Temple University, Philadelphia, Pennsylvania.
Am J Physiol Heart Circ Physiol. 2020 Jun 1;318(6):H1559-H1569. doi: 10.1152/ajpheart.00129.2020. Epub 2020 May 8.
Cerebrovascular dysfunction is a critical risk factor for the pathogenesis of Alzheimer's disease (AD). The purinergic P2Y2 receptor and endoplasmic reticulum (ER) stress are tightly associated with vascular dysfunction and the pathogenesis of AD. However, the protective effects of exercise training on P2Y2 receptor- and ER stress-associated cerebrovascular dysfunction in AD are mostly unknown. Control (C57BL/6, CON) and AD (APP/PS1dE9, AD) mice underwent treadmill exercise training (EX). 2-MeS-ATP-induced dose-dependent vasoreactivity was determined by using a pressurized posterior cerebral artery (PCA) from 10-12-mo-old mice. Human brain microvascular endothelial cells (HBMECs) were exposed to laminar shear stress (LSS) at 20 dyn/cm for 30 min, 2 h, and 24 h. The expression of P2Y2 receptors, endothelial nitric oxide synthase (eNOS), and ER stress signaling were quantified by Western blot analysis. Notably, exercise converted ATP-induced vasoconstriction in the PCA from AD mice to vasodilation in AD+EX mice to a degree commensurate to the vascular reactivity observed in CON mice. Exercise reduced the expression of amyloid peptide precursor (APP) and increased the P2Y2 receptor and Akt/eNOS expression in AD mice brain. Mechanistically, LSS increased the expression of both P2Y2 receptor and eNOS protein in HBMECs, but these increases were blunted by a P2Y2 receptor antagonist in HBMECs. Exercise also reduced the expression of aberrant ER stress markers p-IRE1, p/t-eIF2α, and CHOP, as well as Bax/Bcl-2, in AD mice brain. Collectively, our results demonstrate for the first time that exercise mitigates cerebrovascular dysfunction in AD through modulating P2Y2 receptor- and ER stress-dependent endothelial dysfunction. A limited study has investigated whether exercise training can improve cerebrovascular function in Alzheimer's disease. The novel findings of the study are that exercise training improves cerebrovascular dysfunction through enhancing P2Y2 receptor-mediated eNOS signaling and reducing ER stress-associated pathways in AD. These data suggest that exercise training, which regulates P2Y2 receptor and ER stress in AD brain, is a potential therapeutic strategy for Alzheimer's disease.
脑血管功能障碍是阿尔茨海默病（AD）发病机制的关键危险因素。嘌呤能 P2Y2 受体和内质网（ER）应激与血管功能障碍和 AD 的发病机制密切相关。然而，运动训练对 AD 中与 P2Y2 受体和 ER 应激相关的脑血管功能障碍的保护作用大多尚不清楚。控制（C57BL/6，CON）和 AD（APP/PS1dE9，AD）小鼠进行跑步机运动训练（EX）。使用来自 10-12 月龄小鼠的加压大脑后动脉（PCA）来确定 2-MeS-ATP 诱导的剂量依赖性血管反应性。将人脑血管内皮细胞（HBMEC）暴露于层流剪切力（LSS）下 20 dyn/cm2 30 分钟、2 小时和 24 小时。通过 Western blot 分析定量测定 P2Y2 受体、内皮型一氧化氮合酶（eNOS）和 ER 应激信号的表达。值得注意的是，运动将 AD 小鼠 PCA 中由 ATP 诱导的血管收缩转化为 AD+EX 小鼠的血管舒张，程度与 CON 小鼠观察到的血管反应性相当。运动降低了 AD 小鼠脑中淀粉样前体蛋白（APP）的表达，并增加了 P2Y2 受体和 Akt/eNOS 的表达。从机制上讲，LSS 增加了 HBMECs 中 P2Y2 受体和 eNOS 蛋白的表达，但 P2Y2 受体拮抗剂在 HBMECs 中减弱了这些增加。运动还降低了 AD 小鼠脑中异常 ER 应激标志物 p-IRE1、p/t-eIF2α 和 CHOP 以及 Bax/Bcl-2 的表达。总之，我们的研究结果首次表明，运动通过调节 P2Y2 受体和 ER 应激依赖性内皮功能障碍来减轻 AD 中的脑血管功能障碍。一项有限的研究调查了运动训练是否可以改善阿尔茨海默病患者的脑血管功能。该研究的新发现是，运动训练通过增强 AD 中 P2Y2 受体介导的 eNOS 信号传导并减少与 ER 应激相关的途径来改善脑血管功能障碍。这些数据表明，调节 AD 大脑中的 P2Y2 受体和 ER 应激的运动训练是治疗阿尔茨海默病的潜在治疗策略。
