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

被引：146

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

共 98 条

[11] Alzheimer's disease
Scheltens, Philip
De Strooper, Bart
Kivipelto, Miia
Holstege, Henne
Chetelat, Gael
Teunissen, Charlotte E.
Cummings, Jeffrey
van der Flier, Wiesje M.
[J]. LANCET, 2021, 397 (10284) : 1577 - 1590
[12] The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain
Boisvert, Matthew M.
Erikson, Galina A.
Shokhirev, Maxim N.
Allen, Nicola J.
[J]. CELL REPORTS, 2018, 22 (01): : 269 - 285
[13] Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset
Brookmeyer, R
Gray, S
Kawas, C
[J]. AMERICAN JOURNAL OF PUBLIC HEALTH, 1998, 88 (09) : 1337 - 1342
[14] Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
Bu, Guojun
[J]. NATURE REVIEWS NEUROSCIENCE, 2009, 10 (05) : 333 - 344
[15] Extracellular vesicles - Their role in the packaging and spread of misfolded proteins associated with neurodegenerative diseases
Coleman, Bradley M.
Hill, Andrew F.
[J]. SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 2015, 40 : 89 - 96
[16] Biogenesis, Secretion, and Intercellular Interactions of Exosomes and Other Extracellular Vesicles
Colombo, Marina
Raposo, Graca
Thery, Clotilde
[J]. ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, VOL 30, 2014, 30 : 255 - 289
[17] Conway O.J., 2018, ABI3 PLCG2 MISSENSE
[18] Gender Modulates the APOE ε4 Effect in Healthy Older Adults: Convergent Evidence from Functional Brain Connectivity and Spinal Fluid Tau Levels
Damoiseaux, Jessica S.
Seeley, William W.
Zhou, Juan
Shirer, William R.
Coppola, Giovanni
Karydas, Anna
Rosen, Howard J.
Miller, Bruce L.
Kramer, Joel H.
Greicius, Michael D.
[J]. JOURNAL OF NEUROSCIENCE, 2012, 32 (24) : 8254 - 8262
[19] APOE genotype regulates pathology and disease progression in synucleinopathy
Davis, Albert A.
Inman, Casey E.
Wargel, Zachary M.
Dube, Umber
Freeberg, Brittany M.
Galluppi, Alexander
Haines, Jessica N.
Dhavale, Dhruva D.
Miller, Rebecca
Choudhury, Fahim A.
Sullivan, Patrick M.
Cruchaga, Carlos
Perlmutter, Joel S.
Ulrich, Jason D.
Benitez, Bruno A.
Kotzbauer, Paul T.
Holtzman, David M.
[J]. SCIENCE TRANSLATIONAL MEDICINE, 2020, 12 (529)
[20] Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration
Deczkowska, Aleksandra
Keren-Shaul, Hadas
Weiner, Assaf
Colonna, Marco
Schwartz, Michal
Amit, Ido
[J]. CELL, 2018, 173 (05) : 1073 - 1081

← 1 2 3 4 5 6 7 8 9 10 →