An O-glycopeptide participates in the formation of distinct Aβfibril structures and attenuates Aβneurotoxicity.

Abstract

The self-assembly of biomolecules through noncovalent interactions is critical in both physiological and pathological processes, as exemplified by the assembly of amyloid β peptide (Aβ) into oligomers or fibrils in Alzheimer's disease (AD). Developing molecules that can modulate this assembly process holds significant mechanistic and therapeutic potential. In this study, we identified glycopeptides as a class of protein aggregation modulators, showing that β-N-acetylgalactosamine (β-GalNAc)-modified Aβpromotes Aβfibrillation while reducing its toxic oligomers. Using biochemical assays, cryo-EM, and molecular dynamics simulations, we demonstrated that β-GalNAc-modified Aβcoassembles with Aβ, forming unique fibril structures stabilized by both hydrophobic interactions and an organized hydrogen bond network facilitated by the glycopeptide. Importantly, β-GalNAc-modified Aβcan alleviate the neurotoxicity of Aβin neuronal cells and an AD male mouse model. These findings underscore the potential of glycopeptides in regulating amyloid aggregation and provide structural insights for designing molecules targeting amyloid-related pathologies.