Gangliosides are amphipathic lipids that are exclusive and abundant in mammalian brain. They have been shown to be critical in the self-assembly of Amyloid-β (Aβ) peptides whose amyloid aggregation is implicated in the etiology of Alzheimer’s disease. Previous studies have reported on the roles of membrane-bound gangliosides in the induction and acceleration of Aβ fibrillation observed in vivo and in vitro. Here we explore their roles in affecting Aβ self-assembly when their soluble forms encounter Aβ monomers in an aqueous medium where the lipid’s strong amphipathic character is fully manifested. Using dye-binding assays, we demonstrate that gangliosides (specifically GM1) mixed with Aβ, below the lipid’s critical micelle concentrations (CMC) depletes aggregate yield in a concentration-dependent manner. Molecular dynamics simulations are used to explore the structural properties of lower-order Aβ oligomers formed in the presence and absence of GM1 and describe the factors that drive their formation and stability. We show that inferences drawn from simulations are consistent with observations made by 1H, 15N/1H and selective transferred NOE NMR experiments which reveal that GM1 lipid moiety is key to the structural stability of the Aβ-GM1 complexes and its headgroup is critical to keeping them solvated. Pieced together, our findings underline the concerted ability of GM1’s hydrophilic headgroup and hydrophobic lipid moiety to form stable, water-soluble complexes with Aβ that differ from insoluble Aβ aggregates.

Role for soluble gangliosides on amyloid-Β self-assembly

ACS Spring 2022

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