Abstract
Introduction
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.
Objectives
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.
Methods
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.
Results
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.
Conclusion
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.
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Data availability
The availability of all data presented in this study is from authors upon request.
Abbreviations
- AD:
-
Alzheimer’s disease
- Aβ:
-
β-amyloid
- NFTs:
-
Neurofibrillary tangles
- APP:
-
Amyloid precursor protein
- ATP:
-
Adenosine triphosphate
- LC3:
-
Microtubule-associated protein LC3
- TOM20:
-
Translocase of outer membrane 20
- PCA:
-
Principal component analysis
- P62:
-
Sequestosome 1
- PINK1 :
-
PTEN-induced putative kinase 1
- BCA:
-
Bicinchoninic acid
- TEM:
-
Transmission electron microscopy
- MWM:
-
Morris water maze test
- APP/PS1 double transgenic mice:
-
APPswe/PSEN1dE9 (APP/PSI) transgenic Alzheimer’s disease model mice
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Acknowledgements
The 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).
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LSJ and LY were responsible for study design, statistical analysis and manuscript preparation. LSJ, XXM, ZFL, LGX, PY and LXJ conducted experiments. WYY, FJN and LX analyzed data. LSJ, ZX and LY wrote the manuscript. All authors read and approved the manuscript.
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Experiments in mice were performed under Ethical code: CZLS2022061-A of Chongqing University Cancer Hospital.
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Li, S., Wang, Y., Zhang, X. et al. Mitochondrial damage-induced abnormal glucose metabolism with ageing in the hippocampus of APP/PS1 mice. Metabolomics 19, 56 (2023). https://doi.org/10.1007/s11306-023-02023-9
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DOI: https://doi.org/10.1007/s11306-023-02023-9