title: Amyloid-β(25-35) peptides aggregate into cross-β sheets in unsaturated anionic lipid membranes at high peptide concentrations.
abstract: One of the hallmarks of Alzheimer's disease is the formation of protein plaques in the brain, which mainly consist of amyloid-β peptides of different lengths. While the role of these plaques in the pathology of the disease is not clear, the mechanism behind peptide aggregation is a topic of intense research and discussion. Because of their simplicity, synthetic membranes are promising model systems to identify the elementary processes involved. We prepared unsaturated zwitterionic/anionic lipid membranes made of 1-palmitoyl-2-oleoyl-sn-glycero-phosphocholine (POPC) and 1,2-dimyristoyl-sn-glycero-3-phospho-l-serine (DMPS) at concentrations of POPC/3 mol% DMPS containing 0 mol%, 3 mol%, 10 mol%, and 20 mol% amyloid-β25-35 peptides. Membrane-embedded peptide clusters were observed at peptide concentrations of 10 and 20 mol% with a typical cluster size of ∼11 μm. Cluster density increased with peptide concentration from 59 (±3) clusters per mm(2) to 920 (±64) clusters per mm(2), respectively. While monomeric peptides take an α-helical state when embedded in lipid bilayers at low peptide concentrations, the peptides in peptide clusters were found to form cross-β sheets and showed the characteristic pattern in X-ray experiments. The presence of the peptides was accompanied by an elastic distortion of the bilayers, which can induce a long range interaction between the peptides. The experimentally observed cluster patterns agree well with Monte Carlo simulations of long-range interacting peptides. This interaction may be the fundamental process behind cross-β sheet formation in membranes and these sheets may serve as seeds for further growth into amyloid fibrils.
authors.affiliation: Department of Physics and Astronomy, McMaster University, ABB-241, 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada. rheinstadter@mcmaster.ca.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tang
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Alsop
authors.forename: Matilda
authors.initials: M
authors.lastname: Backholm
authors.forename: Hannah
authors.initials: H
authors.lastname: Dies
authors.forename: An-Chang
authors.initials: AC
authors.lastname: Shi
authors.forename: Maikel C
authors.initials: MC
authors.lastname: Rheinstädter
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000838:Anions / Q000737:chemistry; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D008853:Microscopy; D009010:Monte Carlo Method; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D010713:Phosphatidylcholines / Q000737:chemistry; D017433:Protein Structure, Secondary; D014494:Unithiol / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D016229:Amyloid beta-Peptides; D000838:Anions; D008051:Lipid Bilayers; D010446:Peptide Fragments; D010713:Phosphatidylcholines; C074636:amyloid beta-protein (25-35); D014494:Unithiol; C028694:1-palmitoyl-2-oleoylphosphatidylcholine