Li Chaoyang, Cui Kaiyin, Zhu Xinyuan, Wang Shufan, Yang Qing, Fang Guoliang
Exercise Biology Research Center, China Institute of Sport Science, Beijing, China.
Sport Science School, Beijing Sport University, Beijing, China.
Front Neurosci. 2024 Sep 9;18:1453582. doi: 10.3389/fnins.2024.1453582. eCollection 2024.
Alzheimer's disease (AD) is a degenerative disorder of the central nervous system characterized by notable pathological features such as neurofibrillary tangles and amyloid beta deposition. Additionally, the significant iron accumulation in the brain is another important pathological hallmark of AD. Exercise can play a positive role in ameliorating AD, but the mechanism is unclear. The purpose of the study is to explore the effect of regular aerobic exercise iron homeostasis and lipid antioxidant pathway regarding ferroptosis in the prefrontal cortex (PFC) of / (APP/PS1) mice.
Eighty 6-month-old C57BL/6 J and APP/PS1 mice were divided equally into 8-weeks aerobic exercise groups and sedentary groups. Subsequently, Y-maze, Morris water maze test, iron ion detection by probe, Western Blot, ELISA, RT-qPCR, HE, Nissle, Prussian Blue, IHC, IF, and FJ-C staining experiments were conducted to quantitatively assess the behavioral performance, iron levels, iron-metabolism-related proteins, lipid antioxidant-related proteins and morphology in each group of mice.
In APP/PS1 mice, the increase in heme input proteins and heme oxygenase lead to the elevated levels of free iron in the PFC. The decrease in ferritin content by ferritin autophagy fails to meet the storage needs for excess free iron within the nerve cells. Ultimately, the increase of free ferrous iron triggers the Fenton reaction, may lead to ferroptosis and resulting in cognitive impairment in APP/PS1 mice. However, 8-weeks aerobic exercise induce upregulation of the Xc/GPx4 pathway, which can reverse the lipid peroxidation process, thereby inhibiting ferroptosis in APP/PS1 mice.
8 weeks aerobic exercise can improve learning and memory abilities in AD, upregulate GPx4/Xc pathway in PFC to reduce ferroptosis induced by AD.
阿尔茨海默病（AD）是一种中枢神经系统退行性疾病，其特征为神经原纤维缠结和β-淀粉样蛋白沉积等显著病理特征。此外，大脑中大量铁蓄积是AD的另一个重要病理标志。运动可在改善AD方面发挥积极作用，但其机制尚不清楚。本研究的目的是探讨规律有氧运动对阿尔茨海默病（AD）模型小鼠（APP/PS1）前额叶皮质（PFC）中铁稳态及与铁死亡相关的脂质抗氧化途径的影响。
将80只6月龄的C57BL/6 J小鼠和APP/PS1小鼠平均分为8周有氧运动组和久坐组。随后，进行Y迷宫、莫里斯水迷宫试验、探针检测铁离子、蛋白质免疫印迹法、酶联免疫吸附测定、逆转录-定量聚合酶链反应、苏木精-伊红染色、尼氏染色、普鲁士蓝染色、免疫组织化学、免疫荧光和福尔根-姬姆萨染色实验，以定量评估每组小鼠的行为表现、铁水平、铁代谢相关蛋白、脂质抗氧化相关蛋白及形态。
在APP/PS1小鼠中，血红素输入蛋白和血红素加氧酶的增加导致PFC中游离铁水平升高。铁蛋白自噬导致铁蛋白含量降低，无法满足神经细胞内过量游离铁的储存需求。最终，游离亚铁的增加引发芬顿反应，可能导致铁死亡，并导致APP/PS1小鼠认知障碍。然而，8周有氧运动可诱导Xc/GPx4途径上调，这可以逆转脂质过氧化过程，从而抑制APP/PS1小鼠的铁死亡。
8周有氧运动可改善AD小鼠的学习和记忆能力，上调PFC中的GPx4/Xc途径以减少AD诱导的铁死亡。
