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

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.

Brain transcriptomes of zebrafish and mouse Alzheimer's disease knock-in models imply early disrupted energy metabolism

“…Reassuringly, a recent single-cell RNA-seq analysis (in which discrepancies due to differences in cell-type proportions are overcome) of female APOE4 mice showed that expression of oxidative phosphorylation genes is decreased at 12 months of age, particularly in astrocytes. Further dissection of the metabolic phenotype of female APOE4 mice revealed a shift away from oxidative phosphorylation and towards glycolysis for ATP production ( Farmer et al, 2021 ). Remarkably, this result was consistent with observations in human ε 4 -carrying females, who show lower energy expenditure, decreased oxygen consumption and alterations to their plasma metabolomes indicative of increased glycolysis ( Farmer et al, 2021 ).…”

“…Further dissection of the metabolic phenotype of female APOE4 mice revealed a shift away from oxidative phosphorylation and towards glycolysis for ATP production ( Farmer et al, 2021 ). Remarkably, this result was consistent with observations in human ε 4 -carrying females, who show lower energy expenditure, decreased oxygen consumption and alterations to their plasma metabolomes indicative of increased glycolysis ( Farmer et al, 2021 ).…”

Apolipoprotein E and Alzheimer's disease

“…Humanized APOE ε4 female mice show worse cognition than males 200 . A recent study compared female humanized APOE ε4 mice with samples from human plasma 201 . It was found that in mice APOE ε4 is associated with reduced oxidative phosphorylation and increased glycolysis in astrocytes suggesting a shift towards aerobic glycolysis 201 .…”

“…A recent study compared female humanized APOE ε4 mice with samples from human plasma 201 . It was found that in mice APOE ε4 is associated with reduced oxidative phosphorylation and increased glycolysis in astrocytes suggesting a shift towards aerobic glycolysis 201 . Human plasma samples and indirect calorimetry measures supported the data found in mice 201 .…”

“…It was found that in mice APOE ε4 is associated with reduced oxidative phosphorylation and increased glycolysis in astrocytes suggesting a shift towards aerobic glycolysis 201 . Human plasma samples and indirect calorimetry measures supported the data found in mice 201 . Overall, more research needs to focus on sex differences in AD, especially with regards to APOE ε4.…”