Cytotoxicity in amyloid diseases is mediated by small oligomeric species and, in particular, by their interaction with the plasma membrane. The level of toxicity depends from both the physicochemical properties of the protein aggregates and the composition and organization of the cell membrane.
We employed the small peptide HypF-N as a model of amyloidogenic peptide.
Considering these well demonstrated points:
1. HypF-N aggregates in different conditions, producing oligomers with different toxicity
2. cytotoxicity is always triggered by GM1 content in the cell membrane
We studied the interaction of the cell membrane with toxic and nontoxic protein misfolded oligomers by using AFM-based single cell force spectroscopy (SCFS). We quantified the affinity of the different oligomeric species for the lipid and protein fraction of the cell membrane. In particular, we observed, for the first time, that toxic oligomers influence the functionality of a large class of molecules involved in cell adhesion. We demonstrated that the ganglioside GM1 play a pivotal role in this mechanism.