Ganglioside Lipids Inhibit the Aggregation of the Alzheimer’s Related Peptide Amyloid-β

The aggregation of the amyloid- β (A β ) peptides (A β 42/A β 40) into toxic amyloid fibrils and plaques is one of the molecular hallmarks in dementia and Alzheimers 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 while 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 β 42 and A β 40. We find that ganglioside lipids can drastically inhibit the aggregation of A β 42, while in the case of the smaller peptide (A β 40), gangliosides can completely inhibit the aggregation process. Moreover, through kinetic analysis we show that the primary nucleation rate is greatly affected by the addition of gangliosides, and that the presence of these lipids can inhibit the primary nucleation rate of A β 42 by 3 orders of magnitude. By means of viability assays of neuroblastoma cells (SH-SY5Y), we further demonstrate that amyloid fibrils formed in the absence of gangliosides are more toxic to these cells than amyloid fibrils formed in the presence of gangliosides, elucidating the inhibitory and potentially protective role that these lipids can play. Additionally, we show that monomeric A β 40/A β 42 form complexes with gangliosides, but not with other lipids such as POPS, suggesting that formation of ganglioside-A β complexes can act as a potential pathway towards inhibiting amyloid- β aggregation. Taken together, our results provide a quantitative description of how lipid molecules such as gangliosides can inhibit the aggregation of A β and shed light on the key factors that control these processes, especially in view of the fact that declining levels of gangliosides in neurons have been associated with ageing.