Alzheimer's Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways

被引：142

作者：

Zhao, Na ^{[1
]}

Ren, Yingxue ^{[2
]}

Yamazaki, Yu ^{[1
]}

Qiao, Wenhui ^{[1
]}

Li, Fuyao ^{[1
]}

Felton, Lindsey M. ^{[1
]}

Mahmoudiandehkordi, Siamak ^{[3
,4
]}

Kueider-Paisley, Alexandra ^{[3
,4
]}

Sonoustoun, Berkiye ^{[1
]}

Arnold, Matthias ^{[3
,4
,5
]}

Shue, Francis ^{[6
]}

Zheng, Jiaying ^{[6
]}

Attrebi, Olivia N. ^{[1
]}

Martens, Yuka A. ^{[1
]}

Li, Zonghua ^{[1
]}

Bastea, Ligia ^{[7
]}

Meneses, Axel D. ^{[1
]}

Chen, Kai ^{[1
]}

Thompson, J. Will ^{[8
,9
]}

St John-Williams, Lisa ^{[8
]}

Tachibana, Masaya ^{[1
]}

Aikawa, Tomonori ^{[1
]}

Oue, Hiroshi ^{[1
]}

Job, Lucy ^{[1
]}

Yamazaki, Akari ^{[1
]}

Liu, Chia-Chen ^{[1
]}

Storz, Peter ^{[7
]}

Asmann, Yan W. ^{[2
]}

Ertekin-Taner, Nilufer ^{[1
,10
]}

Kanekiyo, Takahisa ^{[1
]}

Kaddurah-Daouk, Rima ^{[3
,4
]}

Bu, Guojun ^{[1
,6
]}

机构：

[1] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[2] Mayo Clin, Dept Hlth Sci Res, Jacksonville, FL 32224 USA

[3] Duke Univ, Dept Med, Dept Psychiat & Behav Sci, Durham, NC 27708 USA

[4] Duke Univ, Duke Inst Brain Sci, Durham, NC 27708 USA

[5] German Res Ctr Environm Hlth, Inst Bioinformat & Syst Biol, Helmholtz Zentrum Munchen, D-85764 Neuherberg, Bavaria, Germany

[6] Mayo Clin, Neurosci Grad Program, Jacksonville, FL 32224 USA

[7] Mayo Clin, Dept Canc Biol, Jacksonville, FL 32224 USA

[8] Duke Univ, Ctr Genom & Computat Biol, Duke Prote & Metabol Shared Resource, Durham, NC 27708 USA

[9] Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27701 USA

[10] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA

来源：

NEURON | 2020年 / 106卷 / 05期

关键词：

APOLIPOPROTEIN-E GENOTYPE; UNFOLDED PROTEIN RESPONSE; AMYLOID DEPOSITS; UNITED-STATES; A-BETA; DISEASE; ALPHA-1-ANTICHYMOTRYPSIN; BRAIN; MICROGLIA; RECEPTORS;

D O I：

10.1016/j.neuron.2020.02.034

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：727 / +

页数：22

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