Abstract
Glycomics is the study of complex carbohydrates throughout their metabolic lifecycle; precise profiling of these oligosaccharides has been shown to provide a critical understanding of the current state of a disease. N-linked glycans are a subset of the glycome containing co-translational modifications found on cell surface, secreted, and circulating proteins. Prior research shows glycosylation perturbations in Alzheimer's disease (AD), however, these patterns have not been extensively studied in specific brain regions with underlying disease pathology. Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) is a revolutionary technique that combines traditional mass spectrometry with high-resolution imaging to visualize microenvironmental glycan distribution. Using our improved, enzyme-assisted workflow, we can define sub-regional N-linked glycan features in multiple areas of the brain implicated in AD pathogenesis including the hippocampus and the frontal cortex. We saw a profound hyper N-linked glycosylation pattern in multiple (n=4) 5xFAD mouse model (beta-amyloid pathology) brain regions compared to age- and sex-matched, heterozygous littermate controls. Consistent with our in vivo findings, MALDI-MSI analysis of human AD hippocampus and frontal cortex tissue samples revealed a similar hyper glycosylation phenotype. Our studies suggest that beta-amyloid is a metabolic modifier of N-linked glycosylation and could be an exciting therapeutic approach as well as a potential biomarker for AD progression. In the future, we plan to use these results to further investigate specific glycosylation pathways that promote AD pathogenesis, and how these modifications contribute to ER stress and the unfolded protein response, inflammation, and neuronal cell death.
Published Version
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