Lipid composition influences the release of Alzheimer's amyloid β-peptide from membranes

The behavior of the amyloid beta-peptide (A beta) within a membrane environment is integral to its toxicity and the progression of Alzheimer's disease. Ganglioside GM1 has been shown to enhance the aggregation of A beta, but the underlying mechanism is unknown. Using atomistic molecular dynamics simulations, we explored the interactions between the 40-residue alloform of A beta (A beta(40)) and several model membranes, including pure palmitoyloleoylphosphatidylcholine (POPC) and palmitoyloleoylphosphatidylserine (POPS), an equimolar mixture of POPC and palmitoyloleoylphosphatidylethanolamine (POPE), and lipid rafts, both with and without GM1, to understand the behavior of A beta(40) in various membrane microenvironments. A beta(40) remained inserted in POPC, POPS, POPC/POPE, and raft membranes, but in several instances exited the raft containing GM1. A beta(40) interacted with GM1 largely through hydrogen bonding, producing configurations containing beta-strands with C-termini that, in some cases, exited the membrane and became exposed to solvent. These observations provide insight into the release of A beta from the membrane, a previously uncharacterized process of the A beta aggregation pathway.