Hao Zikang, Guo Xinmeng, Wu Jiawen, Yang Guang
Department of Sport and Health, School of Physical Education, Shandong University, Jinan, China.
Kunshan Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China.
Aging Dis. 2024 Dec 24. doi: 10.14336/AD.2024.1560.
Ferroptosis, an iron-dependent form of programmed cell death driven by oxidative stress, plays a crucial role in the progression of Alzheimer's disease (AD). Aging diminishes antioxidant systems that maintain iron homeostasis, particularly affecting the glutathione peroxidase (GPX) system, leading to increased ferroptosis and exacerbated neurodegeneration and neuroinflammation in AD. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor regulating genes involved in antioxidant defense and ferroptosis. In this review, we examine the interconnected roles of Nrf2 signaling, iron metabolism, and ferroptosis in AD, and discuss how regular physical exercise-known to enhance antioxidant capacity-might influence these processes. Despite evidence linking exercise to improved cognitive function in AD and its role in modulating oxidative stress, there is a paucity of research specifically addressing how exercise affects ferroptosis in the AD brain. To address this gap, we utilized bioinformatics techniques to identify potential pathways and mechanisms by which exercise may mitigate ferroptosis in AD through Nrf2 signaling. Analyzing gene expression profiles from the GEO database, we identified differentially expressed ferroptosis-related genes in the hippocampus following exercise intervention. Hub genes like SLC2A1, TXN, MEF2C, and KRAS were significantly upregulated, suggesting that exercise may activate a network enhancing antioxidant defenses and regulating iron metabolism via Nrf2. Our findings propose a novel mechanism whereby exercise alleviates abnormal ferroptosis in the AD brain through modulation of Nrf2 signaling. This study highlights the need for further research to validate these findings and explore exercise as a therapeutic strategy for AD by targeting ferroptosis.
铁死亡是一种由氧化应激驱动的铁依赖性程序性细胞死亡形式，在阿尔茨海默病（AD）的进展中起关键作用。衰老会削弱维持铁稳态的抗氧化系统，尤其影响谷胱甘肽过氧化物酶（GPX）系统，导致铁死亡增加，AD中的神经退行性变和神经炎症加剧。核因子红细胞2相关因子2（Nrf2）是一种关键转录因子，可调节参与抗氧化防御和铁死亡的基因。在本综述中，我们研究了Nrf2信号传导、铁代谢和铁死亡在AD中的相互关联作用，并讨论了已知能增强抗氧化能力的规律体育锻炼可能如何影响这些过程。尽管有证据表明运动与AD中改善认知功能及其在调节氧化应激中的作用有关，但专门研究运动如何影响AD大脑中铁死亡的研究却很少。为了填补这一空白，我们利用生物信息学技术来确定运动可能通过Nrf2信号传导减轻AD中铁死亡的潜在途径和机制。通过分析来自GEO数据库的基因表达谱，我们确定了运动干预后海马体中差异表达的铁死亡相关基因。SLC2A1、TXN、MEF2C和KRAS等枢纽基因显著上调，表明运动可能通过Nrf2激活一个增强抗氧化防御和调节铁代谢的网络。我们的研究结果提出了一种新机制，即运动通过调节Nrf2信号传导减轻AD大脑中的异常铁死亡。这项研究强调需要进一步研究来验证这些发现，并探索将运动作为一种通过靶向铁死亡来治疗AD的策略。
