Lipid membrane templates the ordering and induces the fibrillogenesis of Alzheimer's disease amyloid-beta peptide.
The lipid membrane has been shown to mediate the fibrillogenesis and toxicity of Alzheimer's disease (AD) amyloid-beta (Abeta) peptide. Electrostatic interactions between Abeta40 and the phospholipid headgroup have been found to control the association and insertion of monomeric Abeta into lipid monolayers, where Abeta exhibited enhanced interactions with charged lipids compared with zwitterionic lipids. To elucidate the molecular-scale structural details of Abeta-membrane association, we have used complementary X-ray and neutron scattering techniques (grazing-incidence X-ray diffraction, X-ray reflectivity, and neutron reflectivity) in this study to investigate in situ the association of Abeta with lipid monolayers composed of either the anionic lipid 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (DPPG), the zwitterionic lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), or the cationic lipid 1,2-dipalmitoyl 3-trimethylammonium propane (DPTAP) at the air-buffer interface. We found that the anionic lipid DPPG uniquely induced crystalline ordering of Abeta at the membrane surface that closely mimicked the beta-sheet structure in fibrils, revealing an intriguing templated ordering effect of DPPG on Abeta. Furthermore, incubating Abeta with lipid vesicles containing the anionic lipid 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (POPG) induced the formation of amyloid fibrils, confirming that the templated ordering of Abeta 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 Abeta in vivo. Our results implicate that the adsorption of Abeta 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.
Chi
Eva Y
EY
Department of Chemistry, Institute for Biophysical Dynamics, and The James Franck Institute, The University of Chicago, Chicago, IL 60307, USA.
Ege
Canay
C
Winans
Amy
A
Majewski
Jaroslaw
J
Wu
Guohui
G
Kjaer
Kristian
K
Lee
Ka Yee C
KY
D000327:Adsorption; D000388:Air; D000544:Alzheimer Disease / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000648:ultrastructure; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry / Q000378:metabolism; D005453:Fluorescence; D008051:Lipid Bilayers / Q000737:chemistry*; D009502:Neutrons; D011407:Propane / Q000031:analogs & derivatives / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D012542:Scattering, Radiation; D014867:Water; D014965:X-Rays
C519974:1,2-dipalmitoyl-3-trimethylammonium-propane; D000682:Amyloid; D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D000644:Quaternary Ammonium Compounds; D014867:Water; D011407:Propane; D004134:Dimyristoylphosphatidylcholine