Implications of Mucin-Type O-Glycosylation in Alzheimer's Disease

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders linked to aging. Major hallmarks of AD pathogenesis include amyloid-β peptide (Aβ) plaques, which are extracellular deposits originating from the processing of the amyloid precursor protein (APP), and neurofibrillary tangles (NFTs), which are intracellular aggregates of tau protein. Recent evidence indicates that disruptions in metal homeostasis and impaired immune recognition of these aggregates trigger neuroinflammation, ultimately driving disease progression. Therefore, a more comprehensive approach is needed to understand the underlying causes of the disease. Patients with AD present abnormal glycan profiles, and most known AD-related molecules are either modified with glycans or involved in glycan regulation. A deeper understanding of how O-glycosylation influences the balance between amyloid-beta peptide production and clearance, as well as microglia's pro- and anti-inflammatory responses, is crucial for deciphering the early pathogenic events of AD. This review aims to provide a comprehensive summary of the extensive research conducted on the role of mucin-type O-glycosylation in the pathogenesis of AD, discussing its role in disease onset and immune recognition.