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

Autor:	Zhao N; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: zhao.na@mayo.edu., Ren Y; Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA., Yamazaki Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Qiao W; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Li F; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Felton LM; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Mahmoudiandehkordi S; Department of Psychiatry and Behavioral Sciences, Department of Medicine and the Duke Institute for Brain Sciences, Duke University, Durham, NC 27708, USA., Kueider-Paisley A; Department of Psychiatry and Behavioral Sciences, Department of Medicine and the Duke Institute for Brain Sciences, Duke University, Durham, NC 27708, USA., Sonoustoun B; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Arnold M; Department of Psychiatry and Behavioral Sciences, Department of Medicine and the Duke Institute for Brain Sciences, Duke University, Durham, NC 27708, USA; Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria 85764, Germany., Shue F; Neuroscience Graduate Program, Mayo Clinic, Jacksonville, FL 32224, USA., Zheng J; Neuroscience Graduate Program, Mayo Clinic, Jacksonville, FL 32224, USA., Attrebi ON; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Martens YA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Li Z; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Bastea L; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA., Meneses AD; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Chen K; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Thompson JW; Duke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27701, USA., St John-Williams L; Duke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA., Tachibana M; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Aikawa T; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Oue H; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Job L; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Yamazaki A; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Liu CC; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Storz P; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA., Asmann YW; Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA., Ertekin-Taner N; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA., Kanekiyo T; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Kaddurah-Daouk R; Department of Psychiatry and Behavioral Sciences, Department of Medicine and the Duke Institute for Brain Sciences, Duke University, Durham, NC 27708, USA., Bu G; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Neuroscience Graduate Program, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: bu.guojun@mayo.edu.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2020 Jun 03; Vol. 106 (5), pp. 727-742.e6. Date of Electronic Publication: 2020 Mar 20.
DOI:	10.1016/j.neuron.2020.02.034
Abstrakt:	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. Competing Interests: Declaration of Interests M.A. is co-inventor on patent WO2018049268 in this field. The other authors declare no competing interests. (Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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