Department of Health Toxicology, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong-Road, Wuhan 430030, PR China.
School of Public Health, Guangzhou Medical University, Xinzao, Panyu District, Guangzhou 511436, PR China.
Brain Behav Immun. 2018 Jul;71:66-80. doi: 10.1016/j.bbi.2018.04.014. Epub 2018 Apr 26.
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 (Ser), AT8 (p-tau Ser/Thr) and PHF1 (p-tau Ser) 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.
丙烯酰胺（ACR）是一种轴突毒性物质，可在实验动物和人类中引起周围神经病。 流行病学研究发现，饮食中接触 ACR 与男性轻度认知能力下降有关。 然而，关于其引起记忆改变的潜在机制和机制的信息有限。 姜黄素是一种具有神经保护和认知增强特性的多酚。 在这项研究中，我们旨在研究 ACR 诱导的空间记忆障碍的机制以及姜黄素的有益作用。 ACR 暴露于 10mg/kg/d 7 周导致轻微的步态异常和空间记忆缺陷，这与神经胶质细胞的激活，磷酸化 cAMP 反应元件结合蛋白（P-CREB）的减少以及包括 p-tau（Ser），AT8（p-tau Ser/Thr）和 PHF1（p-tau Ser）在内的过度磷酸化 tau 的聚集有关 在海马体和皮质中。 ACR 明显调节糖原合酶激酶-3β（GSK-3β）和周期蛋白依赖性激酶-5（cdk5）的表达，以加速 tau 过度磷酸化。 ACR 抑制蛋白磷酸酶 2A（PP2A）和溶酶体蛋白酶组织蛋白酶 D，以减少 p-tau 的去磷酸化和降解。 ACR 显著降低了 P-CREB 和脑源性神经营养因子（BDNF）的表达。 P-CREB 的上游信号转导，细胞外信号调节激酶（ERK）和 Akt 明显受到抑制。 蛋白激酶 RNA 样内质网激酶（PERK）-真核起始因子 2α（eIF2α）-激活转录因子 4（ATF4）信号通过抑制 CREB 负性调节记忆过程被 ACR 激活。 姜黄素通过逆转 ACR 在海马体中引起的 tau 异常和 P-CREB 减少来缓解 ACR 引起的空间记忆障碍。 这些结果提供了对机制的更深入了解，并为 ACR 诱导的神经毒性提供了一种潜在的新治疗方法。
