Pathology Department, Shanxi Medical University Fenyang College, Xueyuan Road, Fenyang, Shanxi, 032200, People's Republic of China.
Fenyang Hospital Shanxi Province, Fenyang, 032200, Shanxi, China.
Neurotox Res. 2022 Oct;40(5):1516-1525. doi: 10.1007/s12640-022-00573-9. Epub 2022 Sep 6.
Aluminum neurotoxicity impairs learning and memory ability, but the molecular mechanism has not been elucidated. The aim of this study was to examine the role of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling in regulating the expression of synaptic plasticity-related proteins (PRPs) and p-tau deposition to explore the mechanism underlying aluminum-induced neurotoxicity. We constructed a sub-chronic aluminum-exposed Sprague Dawley (SD) rat model to assess aluminum neurotoxicity in vivo. The learning and memory abilities of rats were examined using the Morris water maze test. We also assessed the effect of aluminum in vitro using rat pheochromocytoma (PC12) cells. To explore the role of PI3K/Akt/mTOR signaling in aluminum neurotoxicity, we used the PI3K inhibitor wortmannin and the mTOR inhibitor rapamycin in aluminum-treated PC12 cells. Protein expression was examined by western blotting. Aluminum disrupted the learning and memory abilities of SD rats. Mechanistically, aluminum reduced the levels of the synaptic PRPs (cAMP-response element binding protein (CREB), glutamate receptor 1 (GluR1), glutamate receptor 2 (GluR2), and postsynaptic density protein 95 (PSD-95), and it increased p-tau deposition in the hippocampus of SD rats. We observed similar results in aluminum-treated PC12 cells. Further, PI3K/Akt/mTOR signaling was abnormally activated in aluminum-treated PC12 cells, and treatment with rapamycin reversed the decrease in synaptic PRPs levels and the increase in p-tau deposition. In conclusion, the activation of PI3K/Akt/mTOR signaling reduces the levels of synaptic PRPs and increases p-tau deposition induced by aluminum. Therefore, the PI3K/Akt/mTOR pathway participates in the mechanism of aluminum neurotoxicity.
铝的神经毒性会损害学习和记忆能力，但分子机制尚未阐明。本研究旨在探讨磷脂酰肌醇 3-激酶（PI3K）/Akt/雷帕霉素靶蛋白（mTOR）信号通路在调节突触可塑性相关蛋白（PRPs）和 p-tau 沉积表达中的作用，以探索铝诱导神经毒性的机制。我们构建了亚慢性铝暴露 Sprague Dawley（SD）大鼠模型，以评估体内铝的神经毒性。使用 Morris 水迷宫测试评估大鼠的学习和记忆能力。我们还使用大鼠嗜铬细胞瘤（PC12）细胞评估了铝的体外效应。为了探讨 PI3K/Akt/mTOR 信号通路在铝神经毒性中的作用，我们在铝处理的 PC12 细胞中使用了 PI3K 抑制剂wortmannin 和 mTOR 抑制剂 rapamycin。通过 Western blot 检测蛋白表达。铝破坏了 SD 大鼠的学习和记忆能力。从机制上讲，铝降低了突触 PRPs（环磷腺苷反应元件结合蛋白（CREB）、谷氨酸受体 1（GluR1）、谷氨酸受体 2（GluR2）和突触后密度蛋白 95（PSD-95）的水平，并增加了 SD 大鼠海马中的 p-tau 沉积。我们在铝处理的 PC12 细胞中也观察到了类似的结果。此外，铝处理的 PC12 细胞中 PI3K/Akt/mTOR 信号通路异常激活，而 rapamycin 处理可逆转突触 PRPs 水平降低和 p-tau 沉积增加。总之，PI3K/Akt/mTOR 信号通路的激活降低了铝诱导的突触 PRPs 水平和 p-tau 沉积的增加。因此，PI3K/Akt/mTOR 通路参与了铝神经毒性的机制。
