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

Abstract

The aggregation of the amyloid-β (Aβ) peptides (Aβ42/Aβ40) 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 Aβ42 and Aβ40. We employ a variety of biophysical assays to characterise the effect ganglioside lipids have on the aggregation of Aβ. Through kinetic analysis, we show that the primary nucleation rate is greatly affected by the addition of gangliosides and that these lipids impair Aβ42 aggregation, while completely inhibiting Aβ40 aggregation. Furthermore, we find that an Aβ-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 Aβ 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-β aggregation.