O-Glycosylation Induces Amyloid-β To Form New Fibril Polymorphs Vulnerable for Degradation

• DOI: 10.1021/jacs.1c08607
• Publication Date: 2021-11-29T10:14:38Z
• Authors: Dangliang Liu; Qijia Wei; Wencheng Xia; Changdong He; Qikai Zhang; Lu Huang; Xiaoya Wang; Yunpeng Sun; Yeyang Ma; Xiaohui Zhang; Yuan Wang; Xiaomeng Shi; Cong Liu; Suwei Dong
• Keywords: Neurotoxicity; Amyloid (mycology); HEK 293 cells; N-linked glycosylation

Brain accumulation of amyloid-β (Aβ) peptides (resulting from a disrupted balance between biosynthesis and clearance) occurs during the progression Alzheimer's disease (AD). Aβ have diverse posttranslational modifications (PTMs) that variously modulate aggregation into fibrils, but understanding mechanistic roles PTMs in these processes remains challenge. Here, we chemically synthesized three homogeneously modified isoforms (1-42) bearing Tyr10 O-glycosylation, an unusual PTM initially identified cerebrospinal fluid samples AD patients. We discovered O-glycans significantly affect both degradation Aβ42. By combining cryo-EM various biochemical assays, demonstrate Galβ1-3GalNAc modification redirects Aβ42 to form new fibril polymorphic structure is less stable more vulnerable Aβ-degrading enzymes (e.g., insulin-degrading enzyme). Thus, beyond showing how particular O-glycosylation at molecular level, our study provides powerful experimental tools support further investigations about AD-related neurotoxicity.