Tau hyperphosphorylation and P-CREB reduction are involved in acrylamide-induced spatial memory impairment: Suppression by curcumin

• Published in: Brain, behavior, and immunity behavior, and immunity, 2018-07, Vol.71, p.66-80
• Main Authors: Yan, Dandan, Yao, Jianling, Liu, Ying, Zhang, Xing, Wang, Yiqi, Chen, Xiaoyi, Liu, Liegang, Shi, Nian, Yan, Hong
• Format: Article
• Language: English
• Subjects: Acrylamide; Acrylamide - pharmacology; Amyloid beta-Peptides - metabolism; Animals; Axons - metabolism; Brain-Derived Neurotrophic Factor - metabolism; Cathepsin D - metabolism; CREB reduction; Curcumin; Curcumin - pharmacology; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic AMP Response Element-Binding Protein - physiology; Cyclin-Dependent Kinase 5 - metabolism; Glycogen Synthase Kinase 3 beta - metabolism; Hippocampus - metabolism; Male; MAP Kinase Signaling System - physiology; Memory Disorders - metabolism; Neurons - metabolism; PERK- eIF2α- ATF4; Phosphorylation; Protein Phosphatase 2 - metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Spatial Memory - drug effects; Spatial Memory - physiology; Spatial memory impairment; Tau phosphorylation; tau Proteins - metabolism
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2018.04.014

•ACR exposure at 10 mg/kg/d for 7 weeks caused spatial memory impairment in rats.•The mechanisms were relied on tau hyperphosphorylation and p-CREB reduction.•Curcumin could alleviate acrylamide-induced spatial memory impairment in rat.•Curcumin reversed ACR-induced tau hyperphosphorylation and P-CREB/BDNF reduction. Acrylamide (ACR) is an axonal toxicant that produces peripheral neuropathy in laboratory animals and humans. Epidemiological study found that diet ACR exposure was associated with a mild cognitive decline in men. However, limited information is available as regards its potential and underlying mechanism to cause memory alterations. Curcumin is a polyphenol with neuroprotective and cognitive-enhancing properties. In this study, we aimed to investigate the mechanism of ACR-induced spatial memory impairment and the beneficial effect of curcumin. ACR exposure at 10 mg/kg/d for 7 weeks caused slight gait abnormality and spatial memory deficits, which was associated with an activation of glial cells, a reduction of phosphorylated cAMP response elements binding protein (P-CREB) and an aggregation of hyperphosphorylated tau including p-tau (Ser262), AT8 (p-tau Ser202/Thr205) and PHF1 (p-tau Ser396/404) in the hippocampus and cortex. ACR markedly regulate the expression of glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase-5 (cdk5) to accelerate tau hyperphosphorylation. ACR inhibited the protein phosphatase 2A (PP2A) and lysosomal protease cathepsin D to decrease the p-tau dephosphorylation and degradation. The P-CREB and brain derived neurotrophic factor (BDNF) were significantly decreased by ACR. The upstream signalings of P-CREB, extracellular signal-related kinase (ERK) and Akt were markedly inhibited. The protein kinase RNA-like endoplasmic reticulum kinase (PERK) -eukaryotic initiation factor-2α (eIF2α) – activating transcription factor 4 (ATF4) signaling which negatively regulate memory processes by suppressing CREB was activated by ACR. Curcumin alleviated ACR-induced spatial memory impairment through reversing tau abnormalities and P-CREB reduction in the hippocampus. These results offered deeper insight into the mechanisms of and presented a potential new treatment for ACR-induced neurotoxicity.