Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation

被引：667

作者：

Johnson, Erik C. B. ^{[1
,2
,3
]}

Dammer, Eric B. ^{[1
,3
]}

Duong, Duc M. ^{[1
,3
]}

Ping, Lingyan ^{[1
,2
,3
]}

Zhou, Maotian ^{[1
,2
,3
]}

Yin, Luming ^{[3
]}

Higginbotham, Lenora A. ^{[2
]}

Guajardo, Andrew ^{[4
]}

White, Bartholomew ^{[4
]}

Troncoso, Juan C. ^{[4
]}

Thambisetty, Madhav ^{[5
,6
]}

Montine, Thomas J. ^{[7
,9
]}

Lee, Edward B. ^{[8
]}

Trojanowski, John Q. ^{[8
]}

Beach, Thomas G. ^{[10
]}

Reiman, Eric M. ^{[9
,10
]}

Haroutunian, Vahram ^{[11
,12
,13
]}

Wang, Minghui ^{[14
]}

Schadt, Eric ^{[14
]}

Zhang, Bin ^{[14
]}

Dickson, Dennis W. ^{[15
]}

Ertekin-Taner, Nilufer ^{[15
,16
]}

Golde, Todd E. ^{[17
]}

Petyuk, Vladislav A. ^{[18
]}

De Jager, Philip L. ^{[19
]}

Bennett, David A. ^{[20
]}

Wingo, Thomas S. ^{[2
,21
]}

Rangaraju, Srikant ^{[2
]}

Hajjar, Ihab ^{[2
]}

Shulman, Joshua M. ^{[22
,23
,24
,25
]}

Lah, James J. ^{[2
]}

Levey, Allan I. ^{[2
,3
]}

Seyfried, Nicholas T. ^{[2
,3
]}

机构：

[1] Emory Univ, Sch Med, Goizueta Alzheimers Dis Res Ctr, Atlanta, GA 30322 USA

[2] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA

[3] Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA

[4] Johns Hopkins Sch Med, Baltimore, MD USA

[5] NIA, Clin & Translat Neurosci Sect, Lab Behav Neurosci, NIH, Bethesda, MD 20892 USA

[6] Stanford Univ, Sch Med, Dept Pathol, Palo Alto, CA 94304 USA

[7] Univ Penn, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res, Perelman Sch Med, Philadelphia, PA USA

[8] Banner Sun Hlth Res Inst, Dept Pathol, Sun City, AZ USA

[9] Arizona State Univ, Banner Alzheimers Inst, Phoenix, AZ USA

[10] Univ Arizona, Phoenix, AZ USA

[11] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[12] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA

[13] MIRECC, JJ Peters VA Med Ctr, Bronx, NY USA

[14] Icahn Sch Med Mt Sinai, Mt Sinai Ctr Transformat Dis Modeling, Dept Genet & Genom Sci, New York, NY 10029 USA

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

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

[17] Univ Florida, Dept Neurosci, Ctr Translat Res Neurodegenerat Dis, McKnight Brain Inst, Gainesville, FL 32610 USA

[18] Pacific Northwest Natl Lab, Div Biol Sci, Richland, WA 99352 USA

[19] Columbia Univ, Dept Neurol, Ctr Translat & Computat Neuroimmunol, Irving Med Ctr,Taub Inst,New York Presbyterian Ho, New York, NY USA

[20] Rush Univ, Rush Alzheimers Dis Ctr, Med Ctr, Chicago, IL 60612 USA

[21] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA

[22] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA

[23] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA

[24] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[25] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA

来源：

NATURE MEDICINE | 2020年 / 26卷 / 05期

基金：

美国国家卫生研究院;

关键词：

RUSH MEMORY; PROTEIN ABUNDANCE; NETWORK APPROACH; COEXPRESSION; QUANTIFICATION; FRAMEWORK; CELL; PET;

D O I：

10.1038/s41591-020-0815-6

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Large-scale, comprehensive proteomic profiling of Alzheimer's disease brain and cerebrospinal fluid reveals disease-associated protein coexpression modules and highlights the importance of glia and energy metabolism in disease pathogenesis. Our understanding of Alzheimer's disease (AD) pathophysiology remains incomplete. Here we used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study thus far on AD. A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with AD pathology and cognitive impairment. This module was enriched in AD genetic risk factors and in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were elevated in cerebrospinal fluid in early stages of the disease. In this study of >2,000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brains that may serve as therapeutic targets and fluid biomarkers for the disease.

引用

页码：769 / +

页数：29

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