Integrative glycoproteomics reveals protein N-glycosylation aberrations and glycoproteomic network alterations in Alzheimer's disease

• Type of Material: Article
• Authors: Qi Zhang, Emory University; Cheng Ma, Georgia State University; Lih-Shen Chin, Emory University; Lian Li, Emory University
• Language: English
• Date: 2020-09-01
• Publisher: American Association for the Advancement of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.abc5802
• Title of Journal or Parent Work: Science Advances
• Volume: 6
• Issue: 40
• Grant/Funding Information: This work was supported by NIH/National Institute on Aging grant RF1AG057965 (to L.L.) and pilot grant awards from the Emory University Research Committee (to L.L.); Atlanta Clinical and Translational Science Institute (to L.-S.C.). Emory Center for Neurodegenerative Disease Brain Bank was supported in part by NIH grants P50 AG025688 and P30 NS055077.
• Keywords: Expression; Science & Technology - Other Topics; Progression; Sites; Software; Science & Technology; Homeostasis; Mechanisms; Multidisciplinary Sciences
• Research Categories: Health Sciences, Pharmacology; Chemistry, Biochemistry; Health Sciences, Rehabilitation and Therapy; Engineering, Biomedical

Abstract

Protein N-glycosylation plays critical roles in controlling brain function, but little is known about human brain N-glycoproteome and its alterations in Alzheimer's disease (AD). Here, we report the first, large-scale, site-specific N-glycoproteome profiling study of human AD and control brains using mass spectrometry-based quantitative N-glycoproteomics. The study provided a system-level view of human brain N-glycoproteins and in vivo N-glycosylation sites and identified disease signatures of altered N-glycopeptides, N-glycoproteins, and N-glycosylation site occupancy in AD. Glycoproteomics-driven network analysis showed 13 modules of co-regulated N-glycopeptides/ glycoproteins, 6 of which are associated with AD phenotypes. Our analyses revealed multiple dysregulated N-glycosylation-affected processes and pathways in AD brain, including extracellular matrix dysfunction, neuroinflammation, synaptic dysfunction, cell adhesion alteration, lysosomal dysfunction, endocytic trafficking dysregulation, endoplasmic reticulum dysfunction, and cell signaling dysregulation. Our findings highlight the involvement of N-glycosylation aberrations in AD pathogenesis and provide new molecular and system-level insights for understanding and treating AD.