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Comprehensive and Site-Specific Characterization of Protein N-Glycosylation in AD Samples Reveals Its Potential Roles
Xing Xu1, Haiyan Tan2, Kejun Yin1
1School of Chemistry and Biochemistry and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
Analytical Chemistry
|October 3, 2025
Summary
Protein N-glycosylation alterations are linked to Alzheimer's disease (AD) pathogenesis. Reduced glycosylation in AD brains impairs synaptic function and promotes protein aggregation, suggesting N-glycosylation as a therapeutic target.
Area of Science:
- Neuroscience
- Biochemistry
- Proteomics
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive decline.
- Protein glycosylation is increasingly recognized as a factor in AD.
- Site-specific N-glycosylation changes in AD require further investigation.
Purpose of the Study:
- To systematically analyze site-specific N-glycosylation alterations in human AD brain tissue.
- To investigate the functional consequences of these glycosylation changes in AD pathogenesis.
Main Methods:
- Utilized a dendrimer boronic acid (DBA)-based enrichment strategy.
- Employed multiplexed proteomics for systematic analysis of N-glycosylation.
- Analyzed post-mortem human brain tissues from AD cases and healthy controls.
Main Results:
- Identified 3,105 N-glycosylation sites on 1,299 glycoproteins.
- Found upregulation of cholesterol efflux glycoproteins and downregulation of synaptic transmission/ion transport glycoproteins in AD.
- Observed widespread N-glycosylation dysregulation, particularly in ConA-like lectins/glucanases and Zn-dependent exopeptidases domains.
- Identified 161 N-glycosylation sites within aggregation-prone regions (APRs), with reduced glycosylation potentially linked to plaque formation.
- Discovered enrichment of downregulated N-glycosylation sites in synaptic proteins, including ion channels and receptors, suggesting a role in synaptic dysfunction.
Conclusions:
- Loss of N-glycosylation contributes to AD pathogenesis by impairing synaptic transmission and promoting protein aggregation.
- Provides novel insights into glycosylation-dependent neurodegeneration mechanisms.
- Highlights N-glycosylation as a potential therapeutic target for Alzheimer's disease.
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