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Profiling Cerebrospinal Fluid Protein Glycosylation in Alzheimer’s Disease: Toward Novel Biomarker Discovery
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Orientador(es)
Resumo(s)
Alzheimer's disease (AD) is the most predominant form of dementia, primarily affecting older population and characterized by progressive memory loss. Current diagnostic methods, including cerebrospinal fluid (CSF) biomarkers, such as amyloid-β42 and tau proteins levels, lack specificity and treatments focus only on symptom management. Recent research has revealed significant alterations in glycosignatures from the brain and CSF in individuals with Alzheimer’s disease. So, this study aims to investigate the complex glycosylation changes of CSF glycoproteins associated with AD, to offer new insights into disease mechanisms and potential diagnostic and therapeutic targets. Two groups of patients were studied: a group with Mild Cognitive Impairment due to AD (MCIAD) and a control group of MCI patients, negative for Aβ deposition and neurodegeneration (MCICONTROL). Glycomic analysis was performed by lectin and immunoblotting using GNA, EPHA, MAL II, SNA and AAL for glycan residues and anti-Lewisx antibody to detect peripheral fucose. For glycoproteomic analysis, peptide mapping of tryptic peptides was performed by LCMS using a ZenoTOF 7600 mass spectrometer. Protein searches used MSFragger and glycan assignment used GlycomeDB database. Oligomannose, bisecting GlcNAc, sialic acid and fucose, including peripheral fucose residues were detected in MCIAD individuals, as well as significant changes in glycosylation patterns. An increase in bisecting GlcNAc (p=0.0185*) and decreases in fucosylation and α2,3-linked sialylation were observed. No significant changes were found in oligomannose structures. A positive correlation between bisecting GlcNAc levels and total and phosphorylated tau was detected, suggesting its potential utility as an early and specific AD diagnosis biomarker. LC-MS analysis of PTGDS revealed the presence of seven glycan structures of complex and hybrid type across two glycosylation sites. These results support the hypothesis that glycosylation patterns are changed through AD progression and highlight the value of glycan-based biomarkers for improving diagnosis and new therapeutic strategies.
Descrição
Tese de mestrado, Biologia Molecular e Genética, 2025, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Alzheimer’s disease glycosylation lectins biomarkers glycoproteins