Cholesterol-dependent Formation of GM1 Ganglioside-bound Amyloid β-Protein, an Endogenous Seed for Alzheimer Amyloid

Abstract

GM1 ganglioside-bound amyloid β-protein (GM1/Aβ), found in brains exhibiting early pathological changes of Alzheimer's disease (AD) including diffuse plaques, has been suggested to be involved in the initiation of amyloid fibril formation in vivo by acting as a seed. To elucidate the molecular mechanism underlying GM1/Aβ formation, the effects of lipid composition on the binding of Aβ to GM1-containing lipid bilayers were examined in detail using fluorescent dye-labeled human Aβ-(1-40). Increases in not only GM1 but also cholesterol contents in the lipid bilayers facilitated the binding of Aβ to the membranes by altering the binding capacity but not the binding affinity. An increase in membrane-bound Aβ concentration triggered its conformational transition from helix-rich to β-sheet-rich structures. Excimer formation of fluorescent dye-labeled GM1 suggested that Aβ Ap recognizes a GM1 "cluster" in membranes, the formation of which is facilitated by cholesterol. The results of the present study strongly suggested that increases in intramembrane cholesterol content, which are likely to occur during aging, appear to be a risk factor for amyloid fibril formation.