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1.
Cell Rep ; 42(3): 112196, 2023 03 28.
Article in English | MEDLINE | ID: mdl-36871219

ABSTRACT

The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response: two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses in mice expressing human APOE to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNA sequencing (RNA-seq) highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1α expression and a disrupted tricarboxylic acid (TCA) cycle and are inherently pro-glycolytic, while spatial transcriptomics and mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism and provide valuable, interactive resources for discovery and validation research.


Subject(s)
Alzheimer Disease , Microglia , Mice , Animals , Humans , Microglia/metabolism , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Apolipoprotein E4/metabolism , Neuroglia/metabolism , Brain/metabolism , Amyloidogenic Proteins/metabolism , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Mice, Transgenic , Apolipoprotein E3/metabolism
2.
Mol Neurodegener ; 16(1): 62, 2021 09 06.
Article in English | MEDLINE | ID: mdl-34488832

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.


Subject(s)
Aerobiosis , Apolipoprotein E4/physiology , Glucose/metabolism , Glycolysis , Prodromal Symptoms , Adolescent , Adult , Aged , Alzheimer Disease/diagnosis , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Animals , Apolipoprotein E4/genetics , Astrocytes/metabolism , Base Sequence , Brain Chemistry , Cells, Cultured , Early Diagnosis , Energy Metabolism , Female , Gas Chromatography-Mass Spectrometry , Gene Knock-In Techniques , Humans , Metabolomics , Mice , Mice, Transgenic , Middle Aged , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Oxidation-Reduction , Oxidative Phosphorylation , Oxygen Consumption/genetics , Sex Characteristics , Single-Cell Analysis , Young Adult
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