Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine, School of Medicine, Jinan University, No. 601 Avenue Huangpu West, Guangzhou, 510632, Guangdong, China.
Department of Internal Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, Guangdong, China.
Mol Neurobiol. 2022 Nov;59(11):6983-6992. doi: 10.1007/s12035-022-03014-y. Epub 2022 Sep 7.
Oxidative stress is one of the pathological mechanisms of Alzheimer's disease (AD), and ferroptosis has been determined to be involved in neurodegenerative diseases such as AD. Senegenin (Sen) prevents oxidative damage in nerve cells via a mechanism that may be highly related to ferroptosis. However, the mechanism of ferroptosis pathway involvement in AD is unclear. In this study, we established a model of PC12 cytotoxic injury induced by Aβ, and we detected the level of oxidative damage, MMP, and ferroptosis-related protein expression. The results showed that, compared with control group, the level of ROS increased, GPX activities decreased, and MDA levels increased in Aβ group. Aβ could induce mitochondrial depolarization in PC12 cells and Fer-1 could not reverse this damage. WB revealed that Aβ group had increased ACSL4 and PEBP1 proteins, and decreased GPX4 protein. After adding Sen in the model, the level of oxidative damage was reduced, and mitochondrial depolarization was reversed compared with Aβ group. WB suggested that the expression of ACSL4 and PEBP1 proteins decreased, and the expression of GPX4 protein increased by Sen treatment. In conclusion, we found that Sen exhibits strong neuroprotective activity against Aβ induced oxidative damage and lipid metabolic associated with ferroptosis. Inhibiting nerve cell ferroptosis might facilitate the future development of strategies to AD.
氧化应激是阿尔茨海默病（AD）的病理机制之一，铁死亡已被确定与 AD 等神经退行性疾病有关。Senegenin（Sen）通过一种可能与铁死亡高度相关的机制防止神经细胞的氧化损伤。然而，铁死亡通路参与 AD 的机制尚不清楚。在本研究中，我们建立了 Aβ诱导的 PC12 细胞毒性损伤模型，并检测了氧化损伤、MMP 和铁死亡相关蛋白的表达水平。结果表明，与对照组相比，Aβ 组 ROS 水平升高，GPX 活性降低，MDA 水平升高。Aβ 可诱导 PC12 细胞线粒体去极化，而 Fer-1 不能逆转这种损伤。WB 显示 Aβ 组 ACSL4 和 PEBP1 蛋白表达增加，GPX4 蛋白表达减少。在模型中加入 Sen 后，与 Aβ 组相比，氧化损伤水平降低，线粒体去极化得到逆转。WB 表明 Sen 处理可降低 ACSL4 和 PEBP1 蛋白的表达，增加 GPX4 蛋白的表达。综上所述，我们发现 Sen 对 Aβ 诱导的氧化损伤和铁死亡相关的脂质代谢具有很强的神经保护活性。抑制神经细胞铁死亡可能有助于未来开发针对 AD 的策略。
