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

GM1 ganglioside-bound amyloid beta -protein (GM1/A beta), found in brains e xhibiting early pathological changes of Alzheimer's disease (AD) including diffuse plaques, has been suggested to be involved in the initiation of amy loid fibril formation in vivo by acting as a seed. To elucidate the molecul ar mechanism underlying GM1/A beta formation, the effects of lipid composit ion on the binding of A beta to GM1-containing lipid bilayers were examined in detail using fluorescent dye-labeled human A beta-(1-40). Increases in not only GM1 but also cholesterol contents in the lipid bilayers facilitate d the binding of A beta to the membranes by altering the binding capacity b ut not the binding affinity. An increase in membrane-bound A beta concentra tion triggered its conformational transition from helix-rich to beta -sheet -rich structures. Excimer formation of fluorescent dye-labeled GM1 suggeste d that A beta recognizes a GM1 "cluster" in membranes, the formation of whi ch is facilitated by cholesterol, The results of the present study strongly suggested that increases in intramembrane cholesterol content, which are l ikely to occur during aging, appear to be a risk factor for amyloid fibril formation.