α-O-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.