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Unlocking the Sugar Code: Implications and Consequences of Glycosylation in Alzheimer’s Disease and Other Tauopathies

Year: 2025

Type: article

Abstract: Alzheimer’s disease (AD) is the most prevalent cause of dementia, characterized by progressive cognitive decline, amyloid-β (Aβ) plaques, and neurofibrillary tangles composed of hyperphosphorylated tau protein. Other tauopathies, including fronto-temporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), and corti-cobasal degeneration (CBD), share pathological hallmarks centered on abnormal tau biology. Increasing evidence highlights the role of post-translational modifications in modulating these pathogenic processes. Among these, glycosylation, the enzymatic attachment of glycans to proteins or lipids, has emerged as a critical regulator of pro-tein folding, trafficking, aggregation, and clearance. Both N-linked glycosylation (N-glycosylation) and O-linked glycosylation (O-glycosylation) influence tau stabil-ity, Aβ processing, receptor signaling, synaptic integrity, and neuroinflammation. Dysregulated glycosylation patterns have been documented in brains and cerebrospi-nal fluid (CSF) of AD patients, suggesting biomarker potential and novel therapeutic targets. Moreover, glycosyltransferases and glycosidases show altered expression in neurodegeneration, linking metabolic and inflammatory pathways to tauopathy pro-gression. This review synthesizes current evidence on the implications and conse-quences of glycosylation in AD and other tauopathies, integrating mechanistic, pathological, and clinical findings. We also discuss advances in glycoproteomics, the interplay between glycosylation and phosphorylation, and the translational potential of targeting glycosylation pathways for diagnosis and therapy.

Source: Biomedicines

DOI: 10.3390/biomedicines13122884