title: Distinct Membrane Disruption Pathways Are Induced by 40-Residue β-Amyloid Peptides.
abstract: Cellular membrane disruption induced by β-amyloid (Aβ) peptides has been considered one of the major pathological mechanisms for Alzheimer disease. Mechanistic studies of the membrane disruption process at a high-resolution level, on the other hand, are hindered by the co-existence of multiple possible pathways, even in simplified model systems such as the phospholipid liposome. Therefore, separation of these pathways is crucial to achieve an in-depth understanding of the Aβ-induced membrane disruption process. This study, which utilized a combination of multiple biophysical techniques, shows that the peptide-to-lipid (P:L) molar ratio is an important factor that regulates the selection of dominant membrane disruption pathways in the presence of 40-residue Aβ peptides in liposomes. Three distinct pathways (fibrillation with membrane content leakage, vesicle fusion, and lipid uptake through a temporarily stable ionic channel) become dominant in model liposome systems under specific conditions. These individual systems are characterized by both the initial states of Aβ peptides and the P:L molar ratio. Our results demonstrated the possibility to generate simplified Aβ-membrane model systems with a homogeneous membrane disruption pathway, which will benefit high-resolution mechanistic studies in the future. Fundamentally, the possibility of pathway selection controlled by P:L suggests that the driving forces for Aβ aggregation and Aβ-membrane interactions may be similar at the molecular level.
authors.affiliation: From the Department of Chemistry, State University of New York, Binghamton, New York 13902 and.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Delgado
authors.affiliation: From the Department of Chemistry, State University of New York, Binghamton, New York 13902 and.
authors.forename: Katelynne
authors.initials: K
authors.lastname: Doherty
authors.affiliation: From the Department of Chemistry, State University of New York, Binghamton, New York 13902 and.
authors.forename: Qinghui
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: From the Department of Chemistry, State University of New York, Binghamton, New York 13902 and.
authors.forename: Hyeongeun
authors.initials: H
authors.lastname: Kim
authors.affiliation: the Department of Chemistry and Biomolecular Science, Clarkson University, Potsdam, New York 13699.
authors.forename: Dawei
authors.initials: D
authors.lastname: Xu
authors.affiliation: the Department of Chemistry and Biomolecular Science, Clarkson University, Potsdam, New York 13699.
authors.forename: He
authors.initials: H
authors.lastname: Dong
authors.affiliation: From the Department of Chemistry, State University of New York, Binghamton, New York 13902 and.
authors.forename: Christof
authors.initials: C
authors.lastname: Grewer
authors.affiliation: From the Department of Chemistry, State University of New York, Binghamton, New York 13902 and wqiang@binghamton.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Qiang
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D002942:Circular Dichroism; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism*; D018613:Microscopy, Confocal; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D013050:Spectrometry, Fluorescence
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D007473:Ion Channels; D008051:Lipid Bilayers; D008081:Liposomes; D008563:Membrane Lipids; D010446:Peptide Fragments; D010743:Phospholipids; C078592:amyloid beta-protein (1-40)
keywords: Alzheimer disease; NMR; amyloid β; ion channel; liposome; membrane