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Exercise training ameliorates cerebrovascular dysfunction in a murine model of Alzheimer's Disease: Role of the P2Y2 receptor and endoplasmic reticulum stress.

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 effect 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 months old mice. Human brain microvascular endothelial cells (HBMECs) were exposed to laminar shear stress (LSS) at 20 dyne/cm2 for 30 mins, 2 hrs, and 24 hrs. The expression of P2Y2 receptors, endothelial nitric oxide synthase (eNOS), and ER stress signaling were quantified by western blotting. 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-eIF2a, 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.