title: Role of the fast kinetics of pyroglutamate-modified amyloid-β oligomers in membrane binding and membrane permeability.
abstract: Membrane permeability to ions and small molecules is believed to be a critical step in the pathology of Alzheimer's disease (AD). Interactions of oligomers formed by amyloid-β (Aβ) peptides with the plasma cell membrane are believed to play a fundamental role in the processes leading to membrane permeability. Among the family of Aβs, pyroglutamate (pE)-modified Aβ peptides constitute the most abundant oligomeric species in the brains of AD patients. Although membrane permeability mechanisms have been studied for full-length Aβ1-40/42 peptides, these have not been sufficiently characterized for the more abundant AβpE3-42 fragment. Here we have compared the adsorbed and membrane-inserted oligomeric species of AβpE3-42 and Aβ1-42 peptides. We find lower concentrations and larger dimensions for both species of membrane-associated AβpE3-42 oligomers. The larger dimensions are attributed to the faster self-assembly kinetics of AβpE3-42, and the lower concentrations are attributed to weaker interactions with zwitterionic lipid headgroups. While adsorbed oligomers produced little or no significant membrane structural damage, increased membrane permeabilization to ionic species is understood in terms of enlarged membrane-inserted oligomers. Membrane-inserted AβpE3-42 oligomers were also found to modify the mechanical properties of the membrane. Taken together, our results suggest that membrane-inserted oligomers are the primary species responsible for membrane permeability.
authors.affiliation: Department of Bioengineering, University of California at San Diego , La Jolla, California 92093, United States.
authors.forename: Joon
authors.initials: J
authors.lastname: Lee
authors.forename: Alan L
authors.initials: AL
authors.lastname: Gillman
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Kagan
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.forename: Fernando
authors.initials: F
authors.lastname: Teran Arce
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism; D002463:Cell Membrane Permeability; D006801:Humans; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)