Exercise training ameliorates cognitive dysfunction in amyloid beta-injected rat model: possible mechanisms of Angiostatin/VEGF signaling.

Aliasghar Zarezadehmehrizi,Naser Naghdi,Hamid Rajabi,Jonghae Lee,Junyoung Hong,Mohammad Azimi,Reza Gharakhanlu,Yoonjung Park

doi:10.1007/s11011-021-00751-2

Abstract

Vascular endothelial growth factor (VEGF) regulates angio/neurogenesis and also tightly links to the pathogenesis of Alzheimer's disease (AD). Although exercise has a beneficial effect on neurovascular function and cognitive function, the direct effect of exercise on VEGF-related signaling and cognitive deficit in AD is incompletely understood. Therefore, the purpose of this study was to investigate the protective effect of exercise on angiostatin/VEGF cascade and cognitive function in AD model rats. Wistar male rats were randomly divided into five groups: control (CON), injection of DMSO (Sham-CON), CON-exercise (sham-EX), intrahippocampal injection of Aβ (Aβ), and Aβ-exercise (Aβ-EX). Rats in EX groups underwent treadmill exercise for 4weeks, then the cognitive function was measured by the Morris Water Maze (MWM) test. mRNA levels of hypoxia-induced factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2), and angiostatin were determined in hippocampus by RT-PCR. We found that spatial learning and memory were impaired in Aβ-injected rats, but exercise training improved it. Moreover, exercise training increased the reduced mRNA expression level of VEGF signaling, including HIF1α, VEGF, and VEGFR2 in the hippocampus from Aβ-injected rats. Also, the mRNA expression level of angiostatin was elevated in the hippocampus from Aβ-injected rats, and exercise training abrogated its expression. Our findings suggest that exercise training improves cognitive function in Aβ-injected rats, possibly through enhancing VEGF signaling and reducing angiostatin.

Highlights

Alzheimer's disease (AD) is a neurodegenerative disease that is responsible for cognitive dysfunction
We found that the mRNA expression levels of Vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) were significantly diminished in the hippocampus from AD brain compared to CON brain, but these expressions were significantly increased in the hippocampus from AD-EX brain compared to AD brain (p < 0.05; Figs. 3b & c)
The presents findings demonstrate the first evidence that AD pathology and exercise training contribute to the mRNA level of angiostatin in AD brain

Summary

Introduction

Alzheimer's disease (AD) is a neurodegenerative disease that is responsible for cognitive dysfunction. The co-existing of neuritic plaque and CAA in AD brain lead to neuronal impairment and cerebrovascular dysfunction (Hong et al, 2020; Zlokovic, 2011), which induce tissue injury and neuronal death, and resulted in cognitive decline in AD (Bell & Zlokovic, 2009). VEGF expression is regulated by hypoxia-induced factor-1α (HIF-1α), binds to its high- affinity receptor vascular endothelial growth factor receptor 2 (VEGFR2) to exert angiogenesis and neurogenesis (Waltenberger, Claesson-Welsh, Siegbahn, Shibuya, & Heldin, 1994; Zhang et al, 2009). Artery in patients with diabetes, the VEGF expression was negatively correlated the angiostatin expression (Chung et al, 2006). The role of angiostatin and its expression in AD is still unclear

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