Evidence in support of chromosomal sex influencing plasma based metabolome vs APOE genotype influencing brain metabolome profile in humanized APOE male and female mice

Late onset Alzheimer’s disease (LOAD) is a progressive neurodegenerative disease with four well-established risk factors: age, APOE4 genotype, female chromosomal sex, and maternal history of AD. Each risk factor impacts multiple systems, making LOAD a complex systems biology challenge. To investigate interactions between LOAD risk factors, we performed multiple scale analyses, including metabolomics, transcriptomics, brain magnetic resonance imaging (MRI), and beta-amyloid assessment, in 16 months old male and female mice with humanized human APOE3 (hAPOE3) or APOE4 (hAPOE4) genes. Metabolomic analyses indicated a sex difference in plasma profile whereas APOE genotype determined brain metabolic profile. Consistent with the brain metabolome, gene and pathway-based RNA-Seq analyses of the hippocampus indicated increased expression of fatty acid/lipid metabolism related genes and pathways in both hAPOE4 males and females. Further, female transcription of fatty acid and amino acids pathways were significantly different from males. MRI based imaging analyses indicated that in multiple white matter tracts, hAPOE4 males and females exhibited lower fractional anisotropy than their hAPOE3 counterparts, suggesting a lower level of white matter integrity in hAPOE4 mice. Consistent with the brain metabolomic and transcriptomic profile of hAPOE4 carriers, beta-amyloid generation was detectable in 16-month-old male and female brains. These data provide therapeutic targets based on chromosomal sex and APOE genotype. Collectively, these data provide a framework for developing precision medicine interventions during the prodromal phase of LOAD, when the potential to reverse, prevent and delay LOAD progression is greatest.

晚发性阿尔茨海默病（Late onset Alzheimer’s disease, LOAD）是一种进行性神经退行性疾病，目前已明确四大危险因素：年龄、APOE4基因型、女性染色体性别以及阿尔茨海默病（Alzheimer’s Disease, AD）母系家族史。各危险因素可累及多个生理系统，使得LOAD成为一项复杂的系统生物学研究难题。
为探究LOAD危险因素间的相互作用，本研究对携带人源化APOE3（hAPOE3）或APOE4（hAPOE4）基因的16月龄雌雄小鼠开展了多维度分析，涵盖代谢组学、转录组学、脑部磁共振成像（Magnetic Resonance Imaging, MRI）以及β-淀粉样蛋白检测。
代谢组学分析结果显示，血浆代谢谱存在性别差异，而脑部代谢谱则由APOE基因型决定。与脑部代谢组学结果一致，对海马体开展的基于基因与通路的RNA测序（RNA-Seq）分析显示，hAPOE4雌雄小鼠体内脂肪酸/脂质代谢相关基因及通路的表达均显著上调。此外，雌性小鼠脂肪酸与氨基酸代谢通路的转录水平与雄性小鼠存在显著差异。
基于磁共振成像的影像分析显示，在多条白质束中，hAPOE4雌雄小鼠的各向异性分数均低于对应hAPOE3小鼠组，提示hAPOE4小鼠的白质完整性水平更低。与hAPOE4携带者的脑部代谢组及转录组特征一致，16月龄雌雄小鼠的脑组织中均可检测到β-淀粉样蛋白生成。
本研究数据为基于染色体性别与APOE基因型的治疗靶点开发提供了依据。综上，本研究数据为在LOAD前驱期开展精准医学干预提供了研究框架——该阶段正是逆转、预防及延缓LOAD进展的最佳窗口期。