Sugar distributions on gangliosides guide the formation and stability of amyloid-β oligomers

Abstract

Aggregation of A{beta} peptides has been known as a key contributor to the etiology of Alzheimers disease. Being intrinsically disordered, the monomeric A{beta} is susceptible to conformational excursions, especially in the presence of key interacting partners such as membrane lipids, to adopt specific aggregation pathways. Furthermore, key components such as gangliosides in membranes and lipid rafts are known to play important roles in the adoption of pathways and the generation of discrete neurotoxic oligomers. Yet, what roles the carbohydrates on gangliosides play in this process remains unknown. Here, using GM1, GM3, and GD3 ganglioside micelles as models, we show that the sugar distributions and cationic amino acids within A{beta} N-terminal region modulate oligomerization of A{beta} temporally, and dictate the stability and maturation of oligomers.