Department of Toxicology, School of Public Health, China Medical University, 92 North 2nd Road, Shenyang 110001, PR China; Shenyang Medical College, 146 Yellow River North Street, Shenyang 110034, PR China; Department of Occupational and Environmental Health, School of Public Health, China Medical University, 92 North 2nd Road, Shenyang 110001, PR China.
Department of Toxicology, School of Public Health, China Medical University, 92 North 2nd Road, Shenyang 110001, PR China.
Toxicology. 2014 Sep 2;323:95-108. doi: 10.1016/j.tox.2014.06.011. Epub 2014 Jun 25.
Epidemiological investigations have indicated that aluminium (Al) is an important environmental neurotoxicant that may be involved in the aetiology of the cognitive dysfunction associated with neurodegenerative diseases. Additionally, exposure to Al is known to cause neurobehavioural abnormalities in animals. Previous studies demonstrated that Al impaired early-phase long-term potentiation (E-LTP) in vivo and in vitro. Our previous research revealed that Al could impair long-term memory via the impairment of late-phase long-term potentiation (L-LTP) in vivo. However, the exact mechanism by which Al impairs long-term memory has been poorly studied thus far. This study was designed not only to observe the effects of subchronic Al treatment on long-term memory and hippocampal ultrastructure but also to explore a possible underlying mechanism (involving the cAMP-PKA-CREB signalling pathway) in the hippocampus of rats.. Pregnant Wistar rats were assigned to four groups. Neonatal rats were exposed to Al by parental lactation for 3 weeks and then fed with distilled water containing 0, 0.2%, 0.4% or 0.6% Al chloride (AlCl3) for 3 postnatal months. The levels of Al in the blood and hippocampus were quantified by atomic absorption spectrophotometry. The shuttle-box test was performed to detect long-term memory. The hippocampus was collected for ultrastructure observation, and the level of cAMP-PKA-CREB signalling was examined. The results showed that the Al concentrations in the blood and hippocampus of Al-treated rats were higher than those of the control rats. Al may impair the long-term memory of rats. Hippocampal cAMP, cPKA, pCREB, BDNF and c-jun expression decreased significantly, and the neuronal and synaptic ultrastructure exhibited pathological changes after Al treatment. These results indicated that Al may induce long-term memory damage in rats by inhibiting cAMP-PKA-CREB signalling and altering the synaptic and neuronal ultrastructure in the hippocampus.
流行病学研究表明，铝（Al）是一种重要的环境神经毒物，可能与神经退行性疾病相关的认知功能障碍的发病机制有关。此外，已知暴露于 Al 会导致动物出现神经行为异常。先前的研究表明，Al 可损害体内和体外的早期长时程增强（E-LTP）。我们之前的研究表明，Al 可通过体内晚期长时程增强（L-LTP）的损害来损害长期记忆。然而，迄今为止，Al 损害长期记忆的确切机制研究甚少。本研究不仅旨在观察亚慢性 Al 处理对长期记忆和海马超微结构的影响，还旨在探讨大鼠海马中可能的潜在机制（涉及 cAMP-PKA-CREB 信号通路）。将怀孕的 Wistar 大鼠分为四组。通过亲代哺乳使新生大鼠暴露于 Al 3 周，然后用含有 0、0.2%、0.4%或 0.6%AlCl3 的蒸馏水喂养 3 个月。采用原子吸收分光光度法测定血液和海马中的 Al 水平。通过穿梭箱测试检测长期记忆。收集海马进行超微结构观察，并检测 cAMP-PKA-CREB 信号通路的水平。结果显示，Al 处理大鼠的血液和海马中的 Al 浓度高于对照组大鼠。Al 可能损害大鼠的长期记忆。海马 cAMP、cPKA、pCREB、BDNF 和 c-jun 表达显著降低，Al 处理后神经元和突触超微结构出现病理改变。这些结果表明，Al 可能通过抑制 cAMP-PKA-CREB 信号通路和改变海马中的突触和神经元超微结构来诱导大鼠的长期记忆损伤。
