Department of Human Anatomy, College of Basic Medicine, Dali University, Xiaguan Campus of Dali University, Wanhua Road, Dali City, Yunnan Province, China.
Department of Computer Network, College of Mathematics and Computer Science, Dali University, Ancient City Campus of Dali University, Wanhua Road, Dali City, Yunnan Province, China.
Mediators Inflamm. 2023 Feb 10;2023:6739691. doi: 10.1155/2023/6739691. eCollection 2023.
Beta-amyloid (A) accumulation in the brains of Alzheimer's disease (AD) patients leads to mitochondrial dysfunction and ferroptosis in neurons. Voltage-dependent anion channel 1 (VDAC1) is a major protein in the mitochondrial outer membrane. It has been reported that VDAC1 associated with mitochondrial dysfunction and ferroptosis. However, the mechanism by which VDAC1 regulates mitochondrial dysfunction and ferroptosis of neurons in AD remains unclear. This study is aimed at investigating the mechanism of action of VDAC1 in mitochondrial dysfunction and ferroptosis in neurons of the AD model. In this study, we determined cell viability after treatment with A via the MTT assay. The SOD, MDA, ROS, and MMP production was measured via the SOD kit, MDA kit, DCFDA staining, and JC-1 staining. The memory abilities of mice were detected via the Morris water maze test. The expression of AMPK/mTOR, Wnt/-catenin, and GPX4 regulated by VDAC1 was detected via western blotting. Our present study showed that PC12 cells had decreased cell viability, increased LDH release, and decreased GPX4 expression after A treatment. Meanwhile, A induced MMP and SOD downregulation and increased MDA and ROS generation in PC12 cells. In addition, the expression of VDAC1 is increased in the brain tissue of AD mice and A -treated PC12 cells. Further investigation of the role of VDAC1 in regulating AD found that all effects induced by A were reversed by inhibition of VDAC1. Additionally, inhibition of VDAC1 activates the AMPK/mTOR and Wnt/-catenin pathways. Taken together, these findings demonstrate that inhibition of VDAC1 alleviates mitochondrial dysfunction and ferroptosis in AD neurons by activating AMPK/mTOR and Wnt/-catenin.
β-淀粉样蛋白（A）在阿尔茨海默病（AD）患者大脑中的积累导致神经元中线粒体功能障碍和铁死亡。电压依赖性阴离子通道 1（VDAC1）是线粒体外膜的主要蛋白质。据报道，VDAC1 与线粒体功能障碍和铁死亡有关。然而，VDAC1 调节 AD 神经元中线粒体功能障碍和铁死亡的机制尚不清楚。本研究旨在研究 VDAC1 在 AD 模型神经元中线粒体功能障碍和铁死亡中的作用机制。在这项研究中，我们通过 MTT 测定法确定了 A 处理后细胞活力。通过 SOD 试剂盒、MDA 试剂盒、DCFDA 染色和 JC-1 染色测定 SOD、MDA、ROS 和 MMP 的产生。通过 Morris 水迷宫测试检测小鼠的记忆能力。通过 Western blot 检测由 VDAC1 调节的 AMPK/mTOR、Wnt/-catenin 和 GPX4 的表达。我们的研究表明，A 处理后 PC12 细胞活力下降，LDH 释放增加，GPX4 表达降低。同时，A 诱导 MMP 和 SOD 下调，增加 PC12 细胞 MDA 和 ROS 的产生。此外，AD 小鼠脑组织和 A 处理的 PC12 细胞中 VDAC1 的表达增加。进一步研究 VDAC1 调节 AD 的作用发现，A 诱导的所有作用均被 VDAC1 抑制所逆转。此外，VDAC1 抑制激活 AMPK/mTOR 和 Wnt/-catenin 途径。综上所述，这些发现表明，抑制 VDAC1 通过激活 AMPK/mTOR 和 Wnt/-catenin 缓解 AD 神经元中线粒体功能障碍和铁死亡。
