| Literature DB >> 32199103 |
Na Zhao1, Yingxue Ren2, Yu Yamazaki3, Wenhui Qiao3, Fuyao Li3, Lindsey M Felton3, Siamak Mahmoudiandehkordi4, Alexandra Kueider-Paisley4, Berkiye Sonoustoun3, Matthias Arnold5, Francis Shue6, Jiaying Zheng6, Olivia N Attrebi3, Yuka A Martens3, Zonghua Li3, Ligia Bastea7, Axel D Meneses3, Kai Chen3, J Will Thompson8, Lisa St John-Williams9, Masaya Tachibana3, Tomonori Aikawa3, Hiroshi Oue3, Lucy Job3, Akari Yamazaki3, Chia-Chen Liu3, Peter Storz7, Yan W Asmann2, Nilüfer Ertekin-Taner10, Takahisa Kanekiyo3, Rima Kaddurah-Daouk4, Guojun Bu11.
Abstract
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.Entities:
Keywords: APOE; Alzheimer’s disease; Serpina3; age; extracellular vesicles; inflammation; lipid metabolism; metabolomics; sex; transcriptomics
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Year: 2020 PMID： 32199103 PMCID： PMC7388065 DOI： 10.1016/j.neuron.2020.02.034
Source DB: PubMed Journal: Neuron ISSN： 0896-6273 Impact factor: 18.688