Abstract

Aluminum (Al), a neurotoxic element, can induce Alzheimer's disease (AD) via triggering neuronal death. Ferroptosis is a new type of programmed cell death related to neurological diseases. Unfortunately, its role in aluminum-induced neuronal death remains completely unclear. This study aimed to investigate whether ferroptosis is involved in neuronal death in response to aluminum exposure as well as its underlying mechanism. In this study, rat adrenal pheochromocytoma (PC12) cells were treated with 200 μM aluminum maltolate (Al(mal)₃) for 24 h, and related biochemical indicators were assessed to determine whether ferroptosis was induced by aluminum in neurons. Then, the potential mechanism was explored by detecting of these genes and proteins associated with ferroptosis after adding ferroptosis-specific agonist Erastin (5 μM) and antagonist Ferrostatin-1 (Fer-1) (5 μM). The experimental results demonstrated that aluminum exposure significantly increased the death of PC12 cells and caused specific mitochondrial pathological changes of ferroptosis in PC12 cells. Further research confirmed that ferroptosis was triggered by aluminum in PC12 cells by means of activating the oxidative damage signaling pathway, which was displayed as inhibition of the cysteine/glutamate antiporter system (system Xc^-), causing the depletion of cellular glutathione (GSH) and inactivation of glutathione peroxidase (GSH-PX) eventually lead to accumulation of reactive oxygen species (ROS). Taken together, ferroptosis was a means of neuronal death induced by aluminum and oxidative damage may be its underlying mechanism, which also provided some new clues to potential target for the intervention and therapy of AD.

摘要

铝（Al）是一种神经毒性元素，可通过触发神经元死亡来诱发阿尔茨海默氏病（AD）。Ferroptosis是与神经系统疾病相关的新型程序性细胞死亡。不幸的是，它在铝诱导的神经元死亡中的作用仍然完全不清楚。这项研究的目的是调查是否铁受铝暴露引起的神经元死亡及其相关的机制。在这项研究中，大鼠肾上腺嗜铬细胞瘤（PC12）细胞用200μM麦芽糖酸铝（Al（mal）₃）持续24小时，并评估相关的生化指标，以确定铝中神经元是否诱发了肥大症。然后，在添加了针对肥大症的特异性激动剂Erastin（5μM）和拮抗剂Ferrostatin-1（Fer-1）（5μM）之后，通过检测与肥大症相关的这些基因和蛋白质，探索了潜在的机制。实验结果表明，铝暴露可显着增加PC12细胞的死亡，并引起PC12细胞受精症的特定线粒体病理变化。进一步研究证实，ferroptosis由铝PC12细胞通过激活氧化损伤信号传导途径，其显示为抑制半胱氨酸/谷氨酸反向转运蛋白系统（系统XC的方式触发^-），导致细胞内的谷胱甘肽（GSH）耗竭和谷胱甘肽过氧化物酶（GSH-PX）失活，最终导致活性氧（ROS）积累。综上所述，肥大症是铝诱导的神经元死亡的一种手段，氧化损伤可能是其潜在的机制，这也为潜在的AD干预和治疗目标提供了新的线索。