Lipid membrane templates the ordering and induces the fibrillogenesis of Alzheimer's disease amyloid-β peptide

The lipid membrane has been shown to mediate the fibrillogenesis and toxicity of Alzheimer's disease (AD) amyloid-P (A beta) peptide. Electrostatic interactions between A beta 40 and the phospholipid headgroup have been found to control the association and insertion of monomeric A beta into lipid monolayers, where A beta exhibited enhanced interactions with charged lipids compared with zwitterionic lipids. To elucidate the molecular-scale structural details of A beta-membrane association, we have used complementary X-ray and neutron scattering techniques (grazing-incidence X-ray diffraction, Xray reflectivity, and neutron reflectivity) in this study to investigate in situ the association of A beta with lipid monolayers composed of either the anionic lipid 1,2-dipalmitoylsn-glycero-3-[phospho-rac-(1-glycerol)] (DPPG), the zwitterionic lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), or the cationic lipid 1,2-dipaimitoyl 3-trimethylammonium propane (DPTAP) at the air-buffer interface. We found that the anionic lipid DPPG uniquely induced crystalline ordering of A beta at the membrane surface that closely mimicked the beta-sheet structure in fibrils, revealing an intriguing templated ordering effect of DPPG on A beta. Furthermore, incubating A beta with lipid vesicles containing the anionic lipid 1-palmitoyl-2-oleoyl-sn-glycero-3-[phosphorac-(1-glycerol)] (POPG) induced the formation of amyloid fibrils, confirming that the templated ordering of A beta at the membrane surface seeded fibril formation. This study provides a detailed molecular-scale characterization of the early structural fluctuation and assembly events that may trigger the misfolding and aggregation of A beta in vivo. Our results implicate that the adsorption of A beta to anionic lipids, which could become exposed to the outer membrane leaflet by cell injury, may serve as an in vivo mechanism of templated-aggregation and drive the pathogenesis of AD.