EXERCISE TRAINING AMELIORATES CEREBROVASCULAR DYSFUNCTION IN ALZHEIMER'S DISEASE; A ROLE OF P2Y2 RECEPTOR AND ENDOPLASMIC RETICULUM STRESS

Abstract

PURPOSE: To determine the protective effect of exercise training on P2Y2 receptor-mediated and ER stress-associated cerebrovascular dysfunction in AD. METHODS: We used the control mice (CON; C57BL/6), CON with exercise training (CON+EX), AD mice (AD; APP/PS1) and AD with EX (AD+EX). At 7 to 9 months of age, CON+EX and AD+EX mice underwent 10-12 weeks of aerobic exercise training on the treadmill, running for an hour at 15m/min at a 5% grade for 5 days a week. To test the purinergic receptor-dependent vasoreactivity, a posterior cerebral artery (PCA) was isolated and pressurized, and then ATP (2-MeS-ATP, 1 nmol/L to 10 μmol/L)-induced dose-dependent vasoreactivities were determined at 10-12 months of age. Human brain micro endothelial cells (HBMECs) were exposed to laminar shear stress (LSS) at 20 dyne/cm2 for 30 mins, 2 hrs, and 24 hrs. Western blotting was utilized to analyze the expression of P2Y2 receptors, endothelial nitric oxide synthesis (eNOS), and ER stress signaling to define the effect of exercise training on cerebrovascular dysfunction. RESULTS: ATP-induced vasodilation in PCA from CON mice, but it caused vasoconstriction in PCA from AD mice. Notably, exercise training reversed ATP-induced vasoconstriction in PCA from AD mice to vasodilation (AD+EX) comparable to CON mice. Exercise training reduced the elevation of APP expression and increased P2Y2 receptor and Akt/eNOS expression in AD mice brain. Also, LSS increased the expression of P2Y2 receptor and eNOS in HBMECS, but these increases were blunted by P2Y2 receptor inhibitor (AR-C) in HBMECs. Exercise training normalized the abnormal expression of ER stress markers; p-IRE1, p/t-eIF2α, CHOP, and ER stress-associated apoptosis; Bax and Bcl-2 in AD mice brain. CONCLUSION: Exercise training improves the cerebrovascular dysfunction in AD possibly through P2Y2 receptor-and ER stress-dependent endothelial dysfunction.