A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer's Disease

• Type of Material: Article
• Authors: Nicholas Seyfried, Emory University; Eric B Dammer, Emory University; Vivek Swarup, University of California Los Angeles; Divya Nandakumar, Emory University; Duc M. Duong, Emory University; Lumin Yin, Emory University; Qiudong Deng, Emory University; Tram Nguyen, Emory University; Chad Hales, Emory University; Thomas Wingo, Emory University; Jonathan D Glass, Emory University; Marla Gearing, Emory University; Madhav Thambisetty, Johns Hopkins School of Medicine; Juan C. Troncoso, Johns Hopkins School of Medicine; Daniel H. Geschwind, University of California Los Angeles; James J Lah, Emory University; Allan I Levey, Emory University
• Language: English
• Date: 2017-01-25
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 The Authors
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cels.2016.11.006
• Title of Journal or Parent Work: Cell Systems
• ISSN: 2405-4720
• Volume: 4
• Issue: 1
• Start Page: 60
• End Page: +
• Grant/Funding Information: This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging.; N.T.S. is supported in part by a Biomarkers Across Neurodegenerative Diseases grant ( 11060 ) funded by the Alzheimer's Association (ALZ), Alzheimer’s Research UK (ARUK), The Michael J. Fox Foundation for Parkinson’s Research (MJFF), and the Weston Brain Institute.; Support for this study was provided by grants from the Accelerating Medicine Partnership AD ( U01AG046161-02 ), the NINDS Emory Neuroscience Core ( P30NS055077 ), the Johns Hopkins Alzheimer’s Disease Research Center( P50AG05146 ), and the Emory Alzheimer's Disease Research Center ( P50AG025688 ).; J.C.T was also supported by a BrightFocus Foundation (A2015332S).
• Keywords: Science & Technology; GENE-EXPRESSION; CELL-TYPE; CEREBRAL-CORTEX; TRANSCRIPTOME; SYSTEMS BIOLOGY; Cell Biology; Biochemistry & Molecular Biology; NEURODEGENERATIVE DISORDERS; FIBRINOGEN; MOLECULAR PATHOLOGY; Life Sciences & Biomedicine; NORMALIZATION; BLOOD-BRAIN-BARRIER
• Research Categories: Chemistry, Biochemistry; Health Sciences, Pathology

Abstract

Here we report proteomic analyses of 129 human cortical tissues to define changes associated with the asymptomatic and symptomatic stages of Alzheimer's disease (AD). Network analysis revealed 16 modules of co-expressed proteins, 10 of which correlated with AD phenotypes. A subset of modules overlapped with RNA co-expression networks, including those associated with neurons and astroglial cell types, showing altered expression in AD, even in the asymptomatic stages. Overlap of RNA and protein networks was otherwise modest, with many modules specific to the proteome, including those linked to microtubule function and inflammation. Proteomic modules were validated in an independent cohort, demonstrating some module expression changes unique to AD and several observed in other neurodegenerative diseases. AD genetic risk loci were concentrated in glial-related modules in the proteome and transcriptome, consistent with their causal role in AD. This multi-network analysis reveals protein- and disease-specific pathways involved in the etiology, initiation, and progression of AD.