APOE4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis

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. 11 to 12-month-old female E3/E3 and E4/E4 mice (pooled n = 3 per genotype) were anesthetized via 5.0% isoflurane before exsanguination and transcardial perfusion with ice-cold Dulbecco's phosphate buffered saline.阿尔茨海默病（Alzheimer's disease, AD）患者，以及携带载脂蛋白E（Apolipoprotein E, APOE）E4等位基因的年轻认知正常个体——该等位基因是晚发性AD最强的遗传预测因子——均会持续表现出大脑葡萄糖代谢减退特征。尽管这一临床特征已被报道二十余年，但大脑葡萄糖代谢改变背后的机制仍是该领域尚未解决的关键科学问题。本研究采用多组学研究策略，结合单细胞RNA测序（single-cell RNA sequencing, scRNAseq）与稳定同位素分辨代谢组学（stable isotope resolved metabolomics, SIRM），对表达APOE4的星形胶质细胞、脑组织、小鼠及人类受试者的代谢重编程过程进行了系统解析。本研究选取11至12月龄的雌性E3/E3及E4/E4基因型小鼠（每组混合3只，每基因型n=3），先以5.0%异氟烷进行麻醉，随后实施放血并以冰冷杜氏磷酸缓冲盐溶液进行经心脏灌注。