Molecular links between aberrant protein oligomers and neurodegeneration in Alzheimer’s disease

Aberrant protein oligomers have been identified as the primary pathogenic agents in many protein deposition disorders includingAlzheimer’s disease. The same polypeptide sequence can assemble into different types of oligomer displaying similar morphologies yet with different abilities to cause cellular dysfunction. The pathogenic nature of oligomeric species results from their ability to diffuse through biological fluids and to interact with cell membranes. Thus, the role of lipid rafts and their ganglioside (notably GM1) content have attracted increasing attention. Here, we quantify the contribution of GM1 content to the cytotoxic effect of two different types of oligomers, grown from the Ab42 peptide associated with Alzheimer’s disease or the model protein HypFN. We found a quantitative relationship between membrane GM1 content in neuroblastoma cells and oligomer binding. In particular, it appears that toxic Ab42 oligomer binding to the cell membrane occurs with high affinity and apparent saturation kinetics whereas the GM1-dependence of non-toxic Ab42 oligomer binding follows linear kinetics and displays low affinity. Similar trends for membrane permeabilization, Ca2+ influx and cell viability were also found in cells with different GM1 content exposed to the oligomers, confirming that the observed cytotoxicity is closely related to oligomer affinity to the membrane. Overall, we provided a robust molecular basis of the role performed by membrane GM1 not only as aggregation promoter but also as key aggregate binding site and hence as initiator of different responses eventually resulting in neurodegeneration. This study was supported by the Fondazione Cassa di Risparmio di Pistoia e Pescia (2014.0251).