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Altered metabolic pathways in a transgenic mouse model suggest mechanistic role of amyloid precursor protein overexpression in Alzheimer’s disease

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Abstract

Introduction

The mechanistic role of amyloid precursor protein (APP) in Alzheimer’s disease (AD) remains unclear.

Objectives

Here, we aimed to identify alterations in cerebral metabolites and metabolic pathways in cortex, hippocampus and serum samples from Tg2576 mice, a widely used mouse model of AD.

Methods

Metabolomic profilings using liquid chromatography-mass spectrometry were performed and analysed with MetaboAnalyst and weighted correlation network analysis (WGCNA).

Results

Expressions of 11 metabolites in cortex, including hydroxyphenyllactate—linked to oxidative stress—and phosphatidylserine—lipid metabolism—were significantly different between Tg2576 and WT mice (false discovery rate < 0.05). Four metabolic pathways from cortex, including glycerophospholipid metabolism and pyrimidine metabolism, and one pathway (sulphur metabolism) from hippocampus, were significantly enriched in Tg2576 mice. Network analysis identified five pathways, including alanine, aspartate and glutamate metabolism, and mitochondria electron transport chain, that were significantly correlated with AD genotype.

Conclusions

Changes in metabolite concentrations and metabolic pathways are present in the early stage of APP pathology, and may be important for AD development and progression.

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Availability of data and materials

The metabolomics and metadata reported in this paper are available via Metabolights (www.ebi.ac.uk/metabolights/MTBLS2280) study identifier MTBLS2280 (Haug et al., 2020).

References

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Acknowledgements

We thank Dr Darren J. Creek and Dr. Dovile Anderson at the Monash Proteomics & Metabolomics Facility (Monash University, Parkville, VIC, Australia) for providing equipment necessary for the experiment and guiding us through the data analysis.

Funding

PK is supported by a Medical Research Future Fund Fellowship; HD is supported by The Scholarship in Commemoration of HM King Bhumibol Adulyadej 90th Birthday Anniversary.

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Authors and Affiliations

Authors

Contributions

HD conceptualized and designed the study, prepared the material and collected the data. Analysis were performed by HD and AH. The first draft of the manuscript was written by HD and all authors commented on previous versions of the manuscript. PK and NJ provided the resources, supervision and funding acquisition. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Patrick Kwan or Nigel C. Jones.

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Conflict of interest

The authors have no conflict of interest—either financial or otherwise—associated with this research.

Research involving human and/or animal participants

This article does not contain any studies involving human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Dejakaisaya, H., Harutyunyan, A., Kwan, P. et al. Altered metabolic pathways in a transgenic mouse model suggest mechanistic role of amyloid precursor protein overexpression in Alzheimer’s disease. Metabolomics 17, 42 (2021). https://doi.org/10.1007/s11306-021-01793-4

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  • DOI: https://doi.org/10.1007/s11306-021-01793-4

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