Ganglioside-mediated aggregation of amyloid β-proteins (Aβ): comparison between Aβ-(1-42) and Aβ-(1-40)

Conversion of the soluble, non-toxic amyloid beta-protein (A beta) into an aggregated, toxic form rich in beta-sheets is considered a key step in the development of Alzheimer's disease. Accumulating evidence suggests that lipid rafts in membranes play a pivotal role in this process. We have proposed that A beta-(1-40) specifically bound to a ganglioside cluster forms cytotoxic fibrils via a conformational transition from an alpha-helix-rich structure to a beta-sheet-rich one. In the present study, we compared the interaction of A beta-(1-40) and A beta-(1-42) with both model and living cell membranes. A beta-(1-42) exhibited lipid specificity and affinity similar to A beta-(1-40), though its amyloidogenic activity was more than 10-fold that of A beta-(1-40). Antibody staining experiments, using the A11 antibody specific to A beta oligomers, demonstrated that oligomers were not detected during the aggregation process, and cell death was observed only after significant accumulation of the proteins, suggesting that the fibril-induced disruption of cell membranes leads to the cytotoxicity. Furthermore, we succeeded in visualizing fibrils formed on cell membranes using total internal reflection fluorescence microscopy. A beta-(140) formed long fibrils extruding to the aqueous phase, whereas A beta-(1-42) fibrils appeared to be laterally co-assembled and short.