No 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.

support-information-section).

Disturbances in the brain's capacity to meet its energy demand increase the risk of synaptic loss, neurodegeneration, and cognitive decline. Nutritional and metabolic interventions that target metabolic pathways combined with diagnostics to identify deficits in cerebral bioenergetics may therefore offer novel therapeutic potential for Alzheimer's disease (AD) prevention and management. Many diet-derived natural bioactive components can govern cellular energy metabolism but their effects on brain aging are not clear. This review examines how nutritional metabolism can regulate brain bioenergetics and mitigate AD risk. We focus on leading mechanisms of cerebral bioenergetic breakdown in the aging brain at the cellular level, as well as the putative causes and consequences of disturbed bioenergetics, particularly at the blood-brain barrier with implications for nutrient brain delivery and nutritional interventions. Novel therapeutic nutrition approaches including diet patterns are provided, integrating studies of the gut microbiome, neuroimaging, and other biomarkers to guide future personalized nutritional interventions.

No abstract

SummaryThe 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 to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNAseq 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, a disrupted TCA cycle, and are inherently pro-glycolytic, while spatial transcriptomics and MALDI 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.

No abstract

BackgroundIndividuals homozygous for the ε4 allele of Apolipoprotein E (APOE) face up to a 15‐fold increase in Alzheimer’s Disease (AD) risk. In comparison, those carrying two ε2 alleles have nearly a 99.6% reduction in risk. Given APOE’s strong risk profile and multitude of effects, APOE itself has emerged as a promising therapeutic target. CRISPR‐Cas9 technology has been used to successfully edit APOE in vitro, where iPSC‐derived glia and neurons edited from ε4 to ε3 show pronounced transcriptional and phenotypic changes. However, whether the putatively beneficial effects of switching to APOE2 holds true in in vivo models has yet to be fully determined.MethodsWe developed a novel transgenic mouse model, the APOE “switch mouse” (4S2) which allows for an inducible (CreERT2) transition from expression of ApoE4 to ApoE2. Gene expression, western blotting, ELISA, and mass spectrometry based proteomic analysis were used to confirm that 4S2 mice synthesize full‐length human ApoE4 at baseline (pre‐switch) and full‐length human ApoE2 after tamoxifen administration (post‐switch). Analysis of plasma lipids, metabolomics, and transcriptomic analyses were used to identify downstream, physiological effects of replacing ApoE4 with ApoE2.ResultsPhysiological phenotyping, gene expression measures, and proteomic analyses further show that following tamoxifen injection, the inducible switch successfully results in efficient (>98%) recombination and expression of human ApoE2. Global genetic replacement of ApoE4 with ApoE2 results in changes to plasma lipids. Mass spec imaging revealed changes in multiple classes of lipids, while single‐cell and spatial RNAseq analyses shows distinct alterations in glial cell transcriptomes. Together these data suggest a successful transition from ApoE4 to ApoE2 that has broad impact on the glial transcriptome as well as on peripheral and cerebral metabolism.ConclusionsOur exciting preliminary studies have leveraged this new mouse as a promising model to assess the feasibility and therapeutic window of replacing APOE4 with APOE2, along with any potential off‐target effects. Ongoing studies aim to determine whether cell‐specific replacement of ApoE4 with APOE2 will rescue E4 associated metabolic dysfunction, disease associated gene signatures, and AD pathology. We hope that this new model will be a valuable resource for the AD/APOE research community.