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Author Notes:

Correspondence: nseyfri@emory.edu (N.T.S.), alevey@emory.edu (A.I.L.)

Conceptualization, N.T.S, E.B.D., A.I.L, J.J.L., and D.H.G

Methodology, D.M.D., E.B.D., and N.T.S.

Investigation, D.M.D., L.Y., T.N., and C.M.H

Formal Analysis, D.N., D.M.D., Q.D., V.S., T.W., and E.B.D.

Writing – Original Draft, N.T.S, E.B.D, and A.I.L.

Writing – Review & Editing, N.T.S, E.B.D, J.J.L., V.S., D.H.G. and A.I.L.

Funding Acquisition, A.I.L and N.T.S.

Resources, J.G., J.C.T, M.G. and M.T.

Supervision, D.H.G. N.T.S, and A.I.L.

We are grateful to participants in the Baltimore Longitudinal Study of Aging and Emory brain bank donors for their invaluable contribution.

We acknowledge Dr. William Hu (Department of Neurology, Emory School of Medicine) and Drs. Giovanni Coppola (Departments of Psychiatry, UCLA), Chris Gaiteri (Rush University), and Sara Mostafavi (University of British Columbia) for helpful comments and discussion.

Subjects:

Research Funding:

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 ).

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.

J.C.T was also supported by a BrightFocus Foundation (A2015332S).

This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology
  • BLOOD-BRAIN-BARRIER
  • NEURODEGENERATIVE DISORDERS
  • MOLECULAR PATHOLOGY
  • SYSTEMS BIOLOGY
  • GENE-EXPRESSION
  • CEREBRAL-CORTEX
  • CELL-TYPE
  • FIBRINOGEN
  • TRANSCRIPTOME
  • NORMALIZATION

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

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Journal Title:

Cell Systems

Volume:

Volume 4, Number 1

Publisher:

, Pages 60-+

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2017 The Authors

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