Chongqing University Cancer Hospital, Chongqing, 400030, P.R. China.
Chongqing Key Laboratory for Intelligent Oncology in Breast Cancer(iCQBC), Chongqing University Cancer Hospital, Chongqing, 400030, P.R. China.
Metabolomics. 2023 Jun 8;19(6):56. doi: 10.1007/s11306-023-02023-9.
Accumulation of β-amyloid (Aβ) in neurons of patients with Alzheimer's disease (AD) inhibits the activity of key enzymes in mitochondrial metabolic pathways, triggering mitochondrial dysfunction, which plays an important role in the onset and development of AD. Mitophagy is a process whereby dysfunctional or damaged mitochondria are removed from the cell. Aberrant mitochondrial metabolism may hinder mitophagy, promote autophagosome accumulation, and lead to neuronal death.
The aim of this experiment is to explore the mechanism of neuronal mitochondria damage in the hippocampus of different age APP/PS1 double transgenic AD mice, and to explore the related metabolites and metabolic pathways for further understanding of the pathogenesis, so as to provide new ideas and strategies for the treatment of AD.
In this study, 24 APP/PS1(APPswe/PSEN1dE9) mice were divided into 3, 6, 9, and 12-month-old groups, and 6-month-old wild-type C57BL/6 mice were as controls. The Morris water maze test was used to evaluate learning and memory. Levels of Aβ were detected by immunohistochemistry. Electron microscopy was used to observe mitochondrial damage and autophagosome accumulation. Western blot was for measuring LC3, P62, PINK1, Parkin, Miro1, and Tom 20 protein expression levels. Gas chromatography coupled with mass spectrometry was used to screen differentially abundant metabolites.
The results showed that with the increase of age in APP/PS1 mice, cognitive impairment, hippocampal neuron mitochondrial damage, and autophagosome accumulation all increased. Furthermore, enhanced mitophagy and impaired mitochondrial clearance leading to metabolic abnormalities were observed with ageing in APP/PS1 mouse hippocampus. Especially, abnormal accumulation of succinic acid and citric acid in the Krebs cycle was observed.
This study investigated the abnormal glucose metabolism associated with age-related damage to mitochondria in the hippocampus of APP/PS1 mice. These findings provide new insights into the pathogenesis of AD.
阿尔茨海默病（AD）患者神经元中β-淀粉样蛋白（Aβ）的积累抑制了线粒体代谢途径中关键酶的活性，引发线粒体功能障碍，这在 AD 的发病和发展中起着重要作用。自噬体是一种将功能失调或受损的线粒体从细胞中清除的过程。异常的线粒体代谢可能会阻碍自噬体的清除，促进自噬体的积累，并导致神经元死亡。
本实验旨在探讨不同年龄 APP/PS1 双转基因 AD 小鼠海马神经元线粒体损伤的机制，并探讨相关代谢物和代谢途径，以进一步了解发病机制，为 AD 的治疗提供新的思路和策略。
本研究将 24 只 APP/PS1（APPswe/PSEN1dE9）小鼠分为 3、6、9 和 12 月龄组，以 6 月龄野生型 C57BL/6 小鼠为对照组。采用 Morris 水迷宫实验评估学习记忆能力。免疫组织化学法检测 Aβ 水平。电镜观察线粒体损伤和自噬体堆积。Western blot 法检测 LC3、P62、PINK1、Parkin、Miro1 和 Tom20 蛋白表达水平。气相色谱-质谱联用技术筛选差异丰度代谢物。
结果显示，随着 APP/PS1 小鼠年龄的增长，认知功能障碍、海马神经元线粒体损伤和自噬体堆积均逐渐加重。此外，随着 APP/PS1 小鼠海马年龄的增长，观察到增强的自噬体和受损的线粒体清除导致代谢异常，特别是 Krebs 循环中琥珀酸和柠檬酸的异常堆积。
本研究探讨了 APP/PS1 小鼠海马与年龄相关的线粒体损伤相关的异常糖代谢，为 AD 的发病机制提供了新的见解。
