Cholesterol-dependent formation of GM1 ganglioside-bound amyloid beta-protein, an endogenous seed for Alzheimer amyloid

GM1 ganglioside-bound amyloid beta-protein (GM1/Abeta), 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/Abeta formation, the effects of lipid composition on the binding of Abeta to GM1-containing lipid bilayers were examined in detail using fluorescent dye-labeled human Abeta-(1-40). Increases in not only GM1 but also cholesterol contents in the lipid bilayers facilitated the binding of Abeta to the membranes by altering the binding capacity but not the binding affinity. An increase in membrane-bound Abeta concentration triggered its conformational transition from helix-rich to beta-sheet-rich structures. Excimer formation of fluorescent dye-labeled GM1 suggested that Abeta 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.