Metabolic fate of glucose in the brain of APP/PS1 transgenic mice at 10 months of age: a 13C NMR metabolomic study
- 164 Downloads
Alzheimer’s disease (AD) has been associated with the disturbance of brain glucose metabolism. The present study investigates brain glucose metabolism using 13C NMR metabolomics in combination with intravenous [1-13C]-glucose infusion in APP/PS1 transgenic mouse model of amyloid pathology at 10 months of age. We found that brain glucose was significantly accumulated in APP/PS1 mice relative to wild-type (WT) mice. Reductions in 13C fluxes into the specific carbon sites of tricarboxylic acid (TCA) intermediate (succinate) as well as neurotransmitters (glutamate, glutamine, γ-aminobutyric acid and aspartate) from [1-13C]-glucose were also detected in the brain of APP/PS1 mice. In addition, our results reveal that the 13C-enrichments of the C3 of alanine were significantly lower and the C3 of lactate have a tendency to be lower in the brain of APP/PS1 mice than WT mice. Taken together, the development of amyloid pathology could cause a reduction in glucose utilization and further result in decreases in energy and neurotransmitter metabolism as well as the lactate-alanine shuttle in the brain.
Keywords13C flux Energy metabolism Brain glucose Neurodegenerative disease Neurotransmitter
13C nuclear magnetic resonance
Morris water maze
Type 1 diabetes
Type 2 diabetes
The Laboratory Animal Center of Wenzhou Medical University was appreciated for technical services.
HZ and HCG contributed to experimental design. QZ, CL and LCZ contributed to animal feeding and intravenous [1-13C]-glucose infusion, QZ, YD, CL and HHX contributed to sample collection and NMR metabolomic analysis. HZ and HCG contributed to data analysis, result interpretation and writing. All authors have read, revised and approved the final manuscript.
This study was supported by the National Natural Science Foundation of China (Nos.: 21605115, 21575105) and the Public Welfare Technology Application Research Foundation of Zhejiang Province (No.: 2017C33066).
Compliance with ethical standards
The authors declare no conflict of interest in this study.
- Cabezas-Opazo FA, Vergara-Pulgar K, Pérez MJ, Jara C, Osorio-Fuentealba C, Quintanilla RA (2015) Mitochondrial dysfunction contributes to the pathogenesis of Alzheimer’s disease. Oxid med cell Longev. 2015, Article ID 509654Google Scholar
- Haberg A, Qu H, Haraldseth O, Unsgard G, Sonnewald U (1998) In vivo injection of [1-13C] glucose and [1,2-13C] acetate combined with ex vivo 13C nuclear magnetic resonance spectroscopy: a novel approach to the study of middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 18(11):1223–1232CrossRefPubMedGoogle Scholar
- Li XY, Men WW, Zhu H, Lei JF, Zuo FX, Wang ZJ, Zhu ZH, Bao XJ, Wang RZ (2016) Age- and brain region-specific changes of glucose metabolic disorder, learning, and memory dysfunction in early Alzheimer’s disease assessed in APP/PS1 transgenic mice using 18F-FDG-PET. Int J Mol Sci 17(10):1707CrossRefPubMedCentralGoogle Scholar
- Wang N, Zhao LC, Zheng YQ, Dong MJ, Su Y, Chen WJ, Hu ZL, Yang YJ, Gao HC (2015) Alteration of interaction between astrocytes and neurons in different stages of diabetes: a nuclear magnetic resonance study using [1-13C] glucose and [2-13C] acetate. Mol Neurobiol 51(3):843–852CrossRefPubMedGoogle Scholar
- Winkler EA, Nishida Y, Sagare AP, Rege SV, Bell RD, Perlmutter D, Sengillo JD, Hillman S, Kong P, Nelson AR, Sullivan JS, Zhao Z, Meiselman HJ, Wenby RB, Soto J, Abel ED, Makshanoff J, Zuniga E, De Vivo DC, Zlokovic BV (2015) GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration. Nat Neurosci 18(4):521–530CrossRefPubMedPubMedCentralGoogle Scholar