TY - JOUR
T1 - Alzheimer's Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways
AU - Zhao, Na
AU - Ren, Yingxue
AU - Yamazaki, Yu
AU - Qiao, Wenhui
AU - Li, Fuyao
AU - Felton, Lindsey M.
AU - Mahmoudiandehkordi, Siamak
AU - Kueider-Paisley, Alexandra
AU - Sonoustoun, Berkiye
AU - Arnold, Matthias
AU - Shue, Francis
AU - Zheng, Jiaying
AU - Attrebi, Olivia N.
AU - Martens, Yuka A.
AU - Li, Zonghua
AU - Bastea, Ligia
AU - Meneses, Axel D.
AU - Chen, Kai
AU - Thompson, J. Will
AU - St John-Williams, Lisa
AU - Tachibana, Masaya
AU - Aikawa, Tomonori
AU - Oue, Hiroshi
AU - Job, Lucy
AU - Yamazaki, Akari
AU - Liu, Chia Chen
AU - Storz, Peter
AU - Asmann, Yan W.
AU - Ertekin-Taner, Nilüfer
AU - Kanekiyo, Takahisa
AU - Kaddurah-Daouk, Rima
AU - Bu, Guojun
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/6/3
Y1 - 2020/6/3
N2 - 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.
AB - 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.
KW - APOE
KW - Alzheimer's disease
KW - Serpina3
KW - age
KW - extracellular vesicles
KW - inflammation
KW - lipid metabolism
KW - metabolomics
KW - sex
KW - transcriptomics
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UR - http://www.scopus.com/inward/citedby.url?scp=85082824401&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2020.02.034
DO - 10.1016/j.neuron.2020.02.034
M3 - Article
C2 - 32199103
AN - SCOPUS:85082824401
SN - 0896-6273
VL - 106
SP - 727-742.e6
JO - Neuron
JF - Neuron
IS - 5
ER -