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

Aggregation of A beta peptides is a key contributor to the etiology of Alzheimer's disease. Being intrinsically disordered, monomeric A beta is susceptible to conformational excursions, especially in the presence of important interacting partners such as membrane lipids, to adopt specific aggregation pathways. Furthermore, 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 do 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. These results demonstrate the selectivity of sugar distributions on the membrane surface toward oligomerization of A beta and thus implicate cell-selective enrichment of oligomers.