• Ming Cai, HuJing YunJYKey Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China., LiuBei BeiBBDepartment of Rehabilitation, Weifang Medical University, Weifang 261053, China; Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China., LiJing JingJJPostdoctoral Station of Clinical Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200082, China., Feng Li, and Shujie Lou.
• College of Rehabilitation Sciences, Shanghai University of Medicine & Health Sciences, Shanghai 201318, China.
• Neuroscience. 2020 Apr 1; 431: 152-165.

AbstractStudies have shown that obesity-induced hyperglycemia and hyperlipidemia could cause increased hippocampal endoplasmic reticulum (ER) stress and impaired cognition-related proteins expression, resulting in learning and memory impairment. Meanwhile, aerobic exercise could activate hippocampal nuclear factor erythroid 2-related factor 2 (Nrf2) reducing ER stress. This study investigated the underlying molecular mechanisms of this effect. In order to clarify the relationship among ER stress, Nrf2 signaling and cognition-related proteins expression in vitro, we respectively treated hippocampal cells with high glucose and palmitic acid (PA), ER stress inhibitor 4-phenylbutyrate (4-PBA), and Nrf2 activator Tert-Butylhydroquinone (TBHQ). Results showed that the expression levels of glucose transporter 3 (GLUT3), fatty acid transport protein 1 (FATP1), ER stress biomarkers (GRP78, p-PERK, p-IRE1α and p-eIF2α), ER stress-mediated apoptosis biomarkers (caspase-12, CHOP and Bax/Bcl-2), and the activity of NLRP3-IL-1β inflammatory pathway were significantly increased under high glucose and PA conditions, accompanied with depressed p38/ERK-CREB pathway and decreased levels of brain derived neurotrophic factor (BDNF) and synaptophysin (SYN). On the other hand, both 4-PBA and TBHQ reduced ER stress and reversed the expression of the above-mentioned proteins. Our findings suggest that high glucose and PA could induce excessive ER stress and apoptosis via promoting the overexpression of GLUT3 and FATP1, and ER stress could suppress BDNF and SYN expression through negatively regulating p38/ERK-CREB pathway and positively regulating NLRP3-IL-1β pathway, which could be reversed by activated Nrf2-HO-1 pathway.Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.

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