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APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis

Posted: Wed Sep 08, 2021 5:29 pm
by BrianR
Open access: https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-021-00483-y

APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis
Molecular Neurodegeneration volume 16, Article number: 62 (2021) [published 6 September 2021]
https://doi.org/10.1186/s13024-021-00483-y

Abstract
Background
Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer’s disease (AD), as well as in young cognitively normal carriers of the Ε4 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.

Methods
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.

Results
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 increased 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 suggest 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 Ε4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing female mice, a subgroup analysis revealed that 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.

Conclusions
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 females decades prior to clinically manifest AD.

Re: APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolys

Posted: Thu Sep 09, 2021 8:38 am
by SusanJ
Cumulatively, these data highlight a novel mechanism whereby Ε4 lowers energy expenditure in young women and decreases glucose oxidation by redirecting flux through aerobic glycolysis.


Interesting article. I plan to reread it when I have a bit more time.

My first take is that there must be some reproductive advantage for E4 females to have this decreased resting energy expenditure.

I'll have to dust off my biochem brain cells and look again at pyruvate metabolism. This one will be next on my reading list.

Regulation of pyruvate metabolism and human disease

Re: APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolys

Posted: Fri Sep 10, 2021 3:58 pm
by BrianR
SusanJ wrote:My first take is that there must be some reproductive advantage for E4 females to have this decreased resting energy expenditure.

Perhaps. Or maybe other advantages offered by APOE4 (enhanced immune activity against parasites?) made up for the side effects.

Re: APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolys

Posted: Sat Sep 11, 2021 9:00 pm
by J11
Alzheimer's as a form of cancer of the brain?
DCA is used in cancer treatment to unblock hyperactive glycolysis.
I wonder whether DCA might also be used in AD.
Perhaps with neuroimaging such an unblocking could be visualized almost immediately in e4 females.
If DCA were formulated with chitosan, then side effects from DCA could be avoided.