title: Influence of sequence and lipid type on membrane perturbation by human and rat amyloid β-peptide (1-42).
abstract: The hallmark characteristics of plaque formation and neuronal cell death in Alzheimer's disease (AD) are caused principally by the amyloid β-peptide (Aβ). Aβ sequence and lipid composition are essential variables to consider when elucidating the impact of biological membranes on Aβ structure and the effect of Aβ on membrane integrity. Atomistic molecular dynamics simulations testing two Aβ sequences, human and rat Aβ (HAβ and RAβ, respectively), and five lipid types were performed to assess the effect of these variables on membrane perturbation and potential link to AD phenotype differences based on differences in sequence. All metrics agree insomuch that monomeric HAβ and RAβ contribute to membrane perturbation by causing a more rigid, gel-like lipid phase. Differences between HAβ and RAβ binding on degree of membrane perturbation were based on lipid headgroup properties. Cholesterol was found to moderate the amount of perturbation caused by HAβ and RAβ in a model raft membrane. The difference in position of an arginine residue between HAβ and RAβ influenced peptide-membrane interactions and was determined to be the mediating factor in observed differences in lipid affinity and degree of membrane disruption. Overall, this work increases our understanding of the influence of sequence and lipid type on Aβ-membrane interactions and their relationship to AD.
authors.affiliation: Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, United States.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Brown
authors.affiliation: Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, United States. Electronic address: drbevan@vt.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Bevan
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry; D000818:Animals; D001120:Arginine / Q000737:chemistry; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry*; D021962:Membrane Microdomains / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D010641:Phenotype; D051381:Rats; D013045:Species Specificity
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008051:Lipid Bilayers; D008055:Lipids; D010446:Peptide Fragments; D001120:Arginine; D002784:Cholesterol
keywords: Alzheimer's disease (AD); Amyloid β-peptide (Aβ); Molecular dynamics simulations; Protein-membrane interactions