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APOE4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

View ORCID ProfileBrandon C. Farmer, View ORCID ProfileHolden C. Williams, View ORCID ProfileNicholas Devanney, Margaret A. Piron, Grant K. Nation, David J. Carter, Adeline E. Walsh, Rebika Khanal, Lyndsay E. A. Young, Jude C. Kluemper, Gabriela Hernandez, Elizabeth J. Allenger, Rachel Mooney, J. Anthony Brandon, Vedant A. Gupta, View ORCID ProfilePhilip A. Kern, View ORCID ProfileMatthew S. Gentry, View ORCID ProfileJosh M. Morganti, View ORCID ProfileRamon C. Sun, View ORCID ProfileLance A. Johnson
doi: https://doi.org/10.1101/2020.10.19.345991
Brandon C. Farmer
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
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Holden C. Williams
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
2Sanders Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA
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Nicholas Devanney
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
2Sanders Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA
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Margaret A. Piron
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
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Grant K. Nation
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
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David J. Carter
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
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Adeline E. Walsh
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
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Rebika Khanal
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
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Lyndsay E. A. Young
3Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA
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Jude C. Kluemper
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
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Gabriela Hernandez
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
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Elizabeth J. Allenger
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
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Rachel Mooney
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
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J. Anthony Brandon
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
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Vedant A. Gupta
4Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, USA
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Philip A. Kern
5Center for Clinical and Translational Science, University of Kentucky College of Medicine, Lexington, KY, USA
6Department of Internal Medicine, Division of Endocrinology, University of Kentucky, Lexington KY
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Matthew S. Gentry
3Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA
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Josh M. Morganti
2Sanders Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA
7Department of Neuroscience, University of Kentucky College of Medicine, Lexington, KY, USA
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Ramon C. Sun
7Department of Neuroscience, University of Kentucky College of Medicine, Lexington, KY, USA
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Lance A. Johnson
1Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
2Sanders Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA
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  • For correspondence: Johnson.Lance@uky.edu
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Abstract

Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer’s disease (AD), as well as in young cognitively normal carriers of the E4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field. Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4. Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of 13C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increases in lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggested an E4 associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the E4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing mice, young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis. Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a ‘Warburg like’ endophenotype that is observable in young humans decades prior to clinically manifest AD.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 20, 2020.
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APOE4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis
Brandon C. Farmer, Holden C. Williams, Nicholas Devanney, Margaret A. Piron, Grant K. Nation, David J. Carter, Adeline E. Walsh, Rebika Khanal, Lyndsay E. A. Young, Jude C. Kluemper, Gabriela Hernandez, Elizabeth J. Allenger, Rachel Mooney, J. Anthony Brandon, Vedant A. Gupta, Philip A. Kern, Matthew S. Gentry, Josh M. Morganti, Ramon C. Sun, Lance A. Johnson
bioRxiv 2020.10.19.345991; doi: https://doi.org/10.1101/2020.10.19.345991
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APOE4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis
Brandon C. Farmer, Holden C. Williams, Nicholas Devanney, Margaret A. Piron, Grant K. Nation, David J. Carter, Adeline E. Walsh, Rebika Khanal, Lyndsay E. A. Young, Jude C. Kluemper, Gabriela Hernandez, Elizabeth J. Allenger, Rachel Mooney, J. Anthony Brandon, Vedant A. Gupta, Philip A. Kern, Matthew S. Gentry, Josh M. Morganti, Ramon C. Sun, Lance A. Johnson
bioRxiv 2020.10.19.345991; doi: https://doi.org/10.1101/2020.10.19.345991

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