Formation of a membrane-active form of amyloid β-protein in raft-like model membranes

Abstract

The conversion of soluble, nontoxic amyloid β-protein (Aβ) to aggregated, toxic Aβ rich in β-sheet structures is considered to be the key step in the development of Alzheimer’s disease. We have proposed that the aggregation proceeds in the lipid raft containing a ganglioside cluster, the formation of which is facilitated by cholesterol and for which Aβ shows a specific affinity. In this study, using fluorescence resonance energy transfer, we found that after Aβ binds to raft-like membranes composed of monosialoganglioside GM1/cholesterol/sphingomyelin (1/1/1), the protein can translocate to the phosphatidylcholine membranes to which soluble Aβ does not bind. Furthermore, self-quenching experiments using fluorescein-labeled Aβ revealed that the translocation process competes with the oligomerization of the protein in the raft-like membranes. These results suggest that the lipid raft containing a ganglioside cluster serves as a conformational catalyst or a chaperon generating a membrane-active form of Aβ with seeding ability.