Effects of membrane interaction and aggregation of amyloid β-peptide on lipid mobility and membrane domain structure

Alzheimer's disease (AD) is the most prevalent age-dependent form of dementia, characterized by extracellular amyloid deposits comprising amyloid beta-peptide (A beta) in the cerebral cortex. Increasing evidence has indicated that ganglioside GM1 (GM1) in lipid rafts plays a pivotal role in amyloid deposition of A beta and the related cytotoxicity in AD. Despite recent efforts to characterize A beta-lipid interactions, the effect of A beta aggregation on dynamic properties and organization of lipid membranes is poorly understood. In this study, we examined the aggregation of A beta on supported lipid bilayers containing raft components (i.e., cholesterol, sphingomyelin, and GM1) and its effects on the membrane properties. We showed that the lateral fluidity of membranes was significantly affected by membrane binding and subsequent aggregation of A beta. Microscopic observations of the membrane surfaces demonstrated an enhancement in phase separation of lipids as a result of interactions between A beta and GM1 during induced aggregation of A beta. The uptake of GM1 into A beta aggregates and the attendant membrane damage were also observed under a microscope when the membrane-anchored aggregates were formed. On the basis of these observations, we propose that A beta aggregates formed in the presence of lipid membranes have a latent ability to trigger the uptake of raft components accompanied by phase separation of lipids.