Glycan-based biomarkers for the diagnostics of Alzheimer´s disease
Biochemistry
Molecular Biology and Physiology of Neurons and Glial Cells
Public Health, Healthcare Research, Social and Occupational Medicine
Final Report Abstract
Alzheimer´s disease (AD), characterized by slow cognitive decline, is the most common neurodegenerative disorder in elderly people. It represents about 70 % of diagnosed cases of dementia. It was estimated in 2021 that 55 million people suffer worldwide from dementia and about 1.6 million Germans suffer from AD, which is about 7% of the elderly German population. As worldwide AD cases are predicted to triple by 2050, it is of high importance to search for novel AD biomarkers. AD neurodegeneration results from the formation of amyloid plaques and from the aggregation of the tau protein. A reduced O-GlcNAcylation occurs that is compensated by hyperphosphorylation, resulting in tau dysfunctions. In addition, glycosylation was previously shown to be modulated in Alzheimer´s disease in mouse models as well as in the CSF of patients using small cohorts: increased bisection and reduced sialic acid content were previously observed. In this project, a cohort of 262 samples including AD cases, other types of dementia and healthy controls was collected by the Peters group. Then, the Blanchard group first investigated the glycome at the level of N-glycans, O-glycans and for the first time also performed a comprehensive study of the free glycans from CSF. Nineteen free N-glycans, 64 N-glycans and 13 O-glycans could be identified. Free glycans consisted of intact and truncated N- and O-glycans. The free glycans Hex1 and HexNAc1Hex1Neu5Ac1 showed the best biomarker potential as judged from the ROC curves: it was possible to discriminate AD patients from healthy controls (area under the curve 0.85 and 0.21) and AD from disease control patients (0.76 and 0.30). Regarding N-glycans, although many differences were gender-specific, the bifucosylated bisected biantennary N-glycan at m/z 2459.2 could statistically differentiate the three patient cohorts from each other for both genders. In addition, the two sialylated N-glycans Neu5Ac1Fuc1Hex5HexNAc4 (at m/z 2605.3) and Neu5Ac1Fuc1Hex4HexNAc5 (at m/z 2646.3) could discriminate Alzheimer´s patients from controls and other forms of dementia for both genders. An article in revision at Biomolecules. Then, a novel high-throughput data-independent acquisition LC-MS technique was developed together with the Ralser group to quantify 1,002 glycopeptides in plasma samples. Finally, the method was applied to our CSF cohort using enriched CSF samples. Over 100 common glycopeptides were differentially expressed in the three cohorts. They were stemming from the amyloid-beta precursor like protein, from acute-phase proteins, cell-adhesion molecules, acute-phase proteins and glycoproteins involved in immune answers. An article is in preparation.
Publications
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Oxonium ion scanning mass spectrometry for large-scale plasma glycoproteomics. Nature Biomedical Engineering, 8(3), 233-247.
White, Matthew E. H.; Sinn, Ludwig R.; Jones, D. Marc; de Folter, Joost; Aulakh, Simran Kaur; Wang, Ziyue; Flynn, Helen R.; Krüger, Lynn; Tober-Lau, Pinkus; Demichev, Vadim; Kurth, Florian; Mülleder, Michael; Blanchard, Véronique; Messner, Christoph B. & Ralser, Markus
