α‐ <i>O</i> ‐Glycosylation at Tyrosine 10 Promotes the Astrocyte Clearance of Amyloid‐β Peptide 1–42

Therapies targeting amyloid β (Aβ), especially promoting Aβ clearance, have attracted increasing attention in treating Alzheimer's disease (AD). However, the regulatory factors in Aβ metabolism remain poorly understood. Herein, three homogeneously glycosylated Aβ₄₂ peptides are utilized to explore the impacts of Tyr10 O-glycosylation on Aβ clearance in astrocytes. Based on various biochemical and cellular assays, it is shown that the introduced α-O-glycan stabilizes the Aβ oligomers and enhances Aβ₄₂ endocytosis and autophagy in astrocytes, which ultimately promotes the intracellular degradation of Aβ₄₂ and the secretion of Aβ-degrading enzymes. Particularly, a disaccharide, Galβ1-3GalNAc, exhibits the most substantial clearance-enhancing effect. Moreover, experiments with AD-like model mice show protective effects from the disaccharide modification in alleviating Aβ₄₂-induced impairment of spatial cognitive performance. Thus, beyond showing the influences induced by particular O-glycosylation on Aβ₄₂ degradation, the study provides implications of a possible role of Tyr10 O-glycan in regulating Aβ clearance in the brain.