Identification of Conserved Proteomic Networks in Neurodegenerative Dementia

• Type of Material: Article
• Authors: Vivek Swarup, University of California Los Angeles; Timothy S Chang, University of California Los Angeles; Duc M Duong, Emory University; Eric Dammer, Emory University; Jingting Dai, Emory University; James Lah, Emory University; Erik Johnson, Emory University; Nicholas Seyfried, Emory University; Allan Levey, Emory University; Daniel H Geschwind, University of California Los Angeles
• Language: English
• Date: 2020-06-23
• Publisher: CELL PRESS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2020.107807
• Title of Journal or Parent Work: CELL REPORTS
• Volume: 31
• Issue: 12
• Start Page: 107807
• End Page: 107807
• Grant/Funding Information: Support for this research was provided by funding from the National Institute of Neurological Disorders and Stroke (NINDS), United States (R25NS065723 Translational Neuroscience Training Grant, P30NS055077 NINDS Emory Neuroscience Core) and National Institute on Aging (NIA), United States (R01AG053960, R01AG057911, R01AG061800, RF1AG057470, RF1AG05747101, U01AG046161 Accelerating Medicine Partnership for Alzheimer’s disease, P50AG025688 Emory Alzheimer’s Disease Research Center).
• Keywords: GENE; BINDING-PROTEIN; Life Sciences & Biomedicine; ALZHEIMERS-DISEASE; HUMAN BRAIN; Science & Technology; FRONTOTEMPORAL DEMENTIA; ANNEXIN A1; ACTIVATION; NEUROPATHOLOGIC ASSESSMENT; NATIONAL INSTITUTE; Cell Biology; PARKINSONS-DISEASE

Abstract

Data-driven analyses are increasingly valued in modern medicine. We integrate quantitative proteomics and transcriptomics from over 1,000 post-mortem brains from six cohorts representing Alzheimer's disease (AD), asymptomatic AD, progressive supranuclear palsy (PSP), and control patients from the Accelerating Medicines Partnership – Alzheimer's Disease consortium. We define robust co-expression trajectories related to disease progression, including early neuronal, microglial, astrocyte, and immune response modules, and later mRNA splicing and mitochondrial modules. The majority of, but not all, modules are conserved at the transcriptomic level, including module C3, which is only observed in proteome networks and enriched in mitogen-activated protein kinase (MAPK) signaling. Genetic risk enriches in modules changing early in disease and indicates that AD and PSP have distinct causal biological drivers at the pathway level, despite aspects of similar pathology, including synaptic loss and glial inflammatory changes. The conserved, high-confidence proteomic changes enriched in genetic risk represent targets for drug discovery. Swarup et al. use a multi-omic, multi-cohort approach to identify robust early and late proteomic changes in AD and other neurodegenerative dementias and find that genetic risk is differentially enriched across disorders. Shared co-expression modules showing consistent molecular alterations at multi-omic levels are ripe for future investigation as drug targets.