The Molecular Mechanisms of Excessive Hippocampal Endoplasmic Reticulum Stress Depressing Cognition-related Proteins Expression and the Regulatory Effects of Nrf2. (1st April 2020)

• Record Type: Journal Article
• Authors: Cai, Ming; Hu, Jing yun; Liu, Bei bei; Li, Jing jing; Li, Feng; Lou, Shujie
• Is Part Of: Neuroscience. Volume 431(2020)
• Page Start: 152
• Page End: 165
• Publication Date: 2020-04-01
• Subjects: 4-PBA 4-phenylbutyrate -- BBB blood brain barrier -- BCM basic culture medium -- BDNF brain derived neurotrophic factor -- ER endoplasmic reticulum -- ERK extracellular signal-related kinase -- FATP1 fatty acid transport protein 1 -- GLUT3 glucose transporter 3 -- IL-1β Interleukin-1β -- Nrf2 nuclear factor erythroid 2-related factor 2 -- PA palmitic acid -- SYN synaptophysin -- TBHQ Tert-Butylhydroquinone -- XBP-1 X-box binding protein 1; high glucose -- high palmitic acid -- hippocampal endoplasmic reticulum stress -- cognition-related proteins -- Nrf2; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2020.02.001
• Languages: English
• ISSNs: 0306-4522

Abstract

Graphical abstract: Highlights: Excessive ER stress could depress cognition-related proteins expression. ER stress could negatively regulate p38/ERK-CREB pathway. ER stress could positively regulate NLRP3-IL-1β pathway. Activating Nrf2 could effectively ease hippocampal ER stress. Abstract: Studies 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.