Integrative glycoproteomics reveals protein N-glycosylation aberrations and glycoproteomic network alterations in Alzheimer's disease.
Qi ZhangCheng MaLih-Shen ChinLian LiPublished in: Science advances (2020)
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.
Keyphrases
- network analysis
- extracellular matrix
- oxidative stress
- mass spectrometry
- single cell
- endoplasmic reticulum
- cell adhesion
- white matter
- endothelial cells
- resting state
- cognitive decline
- stem cells
- copy number
- transcription factor
- cerebral ischemia
- multiple sclerosis
- genome wide
- small molecule
- cognitive impairment
- lps induced
- lipopolysaccharide induced
- ms ms
- single molecule
- simultaneous determination
- brain injury
- high performance liquid chromatography
- genome wide analysis