Ganglioside lipids inhibit the aggregation of the Alzheimer's amyloid-β peptide

The aggregation of the amyloid-beta (A beta) peptides (A beta 42/A beta 40) into amyloid fibrils and plaques is one of the molecular hallmarks in dementia and Alzheimer's disease (AD). While the molecular mechanisms behind this aggregation process are not fully known, it has been shown that some biomolecules can accelerate this process whereas others can inhibit amyloid formation. Lipids, which are ubiquitously found in cell membranes, play a pivotal role in protein aggregation. Here, we investigate how ganglioside lipids, which are abundant in the brain and in neurons, can influence the aggregation kinetics of both A beta 42 and A beta 40. We employ a variety of biophysical assays to characterise the effect ganglioside lipids have on the aggregation of A beta. Through kinetic analysis, we show that the primary nucleation rate is greatly affected by the addition of gangliosides and that these lipids impair A beta 42 aggregation, while completely inhibiting A beta 40 aggregation. Furthermore, we find that an A beta-ganglioside complex is formed, which potentially disrupts the aggregation pathway and results in delayed kinetics. Taken together, our results provide a quantitative description of how lipid molecules such as gangliosides can inhibit the aggregation of A beta and shed light on the key factors that control these processes. In view of the fact that declining levels of gangliosides in neurons have been associated with ageing, our findings could be instrumental towards establishing new approaches in the prevention of amyloid-beta aggregation.