Mitochondrial damage-induced abnormal glucose metabolism with ageing in the hippocampus of APP/PS1 mice

作者全名："Li, Shijie; Wang, Yangyang; Zhang, Xiong; Xiong, Xiaomin; Zhou, Fanlin; Li, Xiaoju; Fan, Jianing; Liang, Xiao; Li, Guangxin; Peng, Yan; Li, Yu"

作者地址："[Li, Shijie; Zhou, Fanlin; Li, Xiaoju; Li, Guangxin; Li, Yu] Chongqing Univ, Canc Hosp, Chongqing 400030, Peoples R China; [Li, Shijie; Zhou, Fanlin; Li, Xiaoju; Li, Guangxin; Li, Yu] Chongqing Univ, Chongqing Key Lab Intelligent Oncol Breast Canc iC, Canc Hosp, Chongqing 400030, Peoples R China; [Wang, Yangyang; Xiong, Xiaomin; Fan, Jianing; Liang, Xiao] Chongqing Univ, Sch Med, Chongqing 400030, Peoples R China; [Zhang, Xiong] Chongqing Med Univ, Basic Med Coll, Chongqing, Peoples R China; [Peng, Yan] Chongqing Med Univ, Sch Basic Med Sci, Teaching & Res Sect Pathol & Pathophysiol, Chongqing 400016, Peoples R China; [Li, Yu] Chongqing Univ, Dept Pathol, Canc Hosp, Hanyu Rd, Chongqing 400030, Peoples R China"

通信作者："Li, Y (通讯作者)，Chongqing Univ, Canc Hosp, Chongqing 400030, Peoples R China.; Li, Y (通讯作者)，Chongqing Univ, Chongqing Key Lab Intelligent Oncol Breast Canc iC, Canc Hosp, Chongqing 400030, Peoples R China.; Li, Y (通讯作者)，Chongqing Univ, Dept Pathol, Canc Hosp, Hanyu Rd, Chongqing 400030, Peoples R China."

来源：METABOLOMICS

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001003494100003

JCR分区：Q2

影响因子：3.5

年份：2023

卷号：19

期号：6

开始页：　

结束页：　

文献类型：Article

关键词：Alzheimer's disease (AD); Hippocampus; Mitochondrial autophagy; Glucose metabolism; Age

摘要："IntroductionAccumulation of beta-amyloid (A beta) 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.ObjectivesThe 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.MethodsIn 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 A beta 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.ResultsThe 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.ConclusionThis 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."

基金机构：The Performance Incentive Guidance for Scientific Research Institution of Chongqing [cstc2020jxjl130013]; Fundamental Research Funds for the Central University [2019CDYGZD002]

基金资助正文：AcknowledgementsThe authors thank all APP/PS1 mice who participated and continue to contribute to ongoing research. This work was supported by The Performance Incentive Guidance for Scientific Research Institution of Chongqing (No. cstc2020jxjl130013); and the Fundamental Research Funds for the Central University (No. 2019CDYGZD002).