Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA.
Neuron. 2020 Jun 3;106(5):727-742.e6. doi: 10.1016/j.neuron.2020.02.034. Epub 2020 Mar 20.
Evidence suggests interplay among the three major risk factors for Alzheimer's disease (AD): age, APOE genotype, and sex. Here, we present comprehensive datasets and analyses of brain transcriptomes and blood metabolomes from human apoE2-, apoE3-, and apoE4-targeted replacement mice across young, middle, and old ages with both sexes. We found that age had the greatest impact on brain transcriptomes highlighted by an immune module led by Trem2 and Tyrobp, whereas APOE4 was associated with upregulation of multiple Serpina3 genes. Importantly, these networks and gene expression changes were mostly conserved in human brains. Finally, we observed a significant interaction between age, APOE genotype, and sex on unfolded protein response pathway. In the periphery, APOE2 drove distinct blood metabolome profile highlighted by the upregulation of lipid metabolites. Our work identifies unique and interactive molecular pathways underlying AD risk factors providing valuable resources for discovery and validation research in model systems and humans.
有证据表明，阿尔茨海默病（AD）的三个主要风险因素（年龄、APOE 基因型和性别）之间存在相互作用。在这里，我们展示了来自人类 apoE2、apoE3 和 apoE4 靶向替换小鼠的大脑转录组和血液代谢组的综合数据集和分析，涵盖了年轻、中年和老年的两个性别。我们发现年龄对大脑转录组的影响最大，其特征是由 Trem2 和 Tyrobp 驱动的免疫模块，而 APOE4 与多个 Serpina3 基因的上调有关。重要的是，这些网络和基因表达变化在人类大脑中大多是保守的。最后，我们观察到未折叠蛋白反应途径中年龄、APOE 基因型和性别之间存在显著的相互作用。在外周组织中，APOE2 驱动了脂质代谢物上调为特征的独特血液代谢组图谱。我们的工作确定了 AD 风险因素的独特和相互作用的分子途径，为模型系统和人类中的发现和验证研究提供了有价值的资源。
