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

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

Automated summary

The study demonstrates that O-glycans significantly impact both the aggregation and degradation of Aβ(42). A Galβ1-3GalNAc modification redirects Aβ(42) to form a new fibril polymorphic structure, which is less stable and more vulnerable to Aβ-degrading enzymes such as the insulin-degrading enzyme.