title: Aggregation-Prone Amyloid-β⋅Cu(II) Species Formed on the Millisecond Timescale under Mildly Acidic Conditions.
abstract: Metal ions and their interaction with the amyloid beta (Aβ) peptide might be key elements in the development of Alzheimer's disease. In this work the effect of Cu(II) on the aggregation of Aβ is explored on a timescale from milliseconds to days, both at physiological pH and under mildly acidic conditions, by using stopped-flow kinetic measurements (fluorescence and light-scattering), (1) H NMR relaxation and ThT fluorescence. A minimal reaction model that relates the initial Cu(II) binding and Aβ folding with downstream aggregation is presented. We demonstrate that a highly aggregation prone Aβ⋅Cu(II) species is formed on the sub-second timescale at mildly acidic pH. This observation might be central to the molecular origin of the known detrimental effect of acidosis in Alzheimer's disease.
authors.affiliation: Department of Pharmaceutics, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark). jeppe.trudslev@sund.ku.dk.
authors.forename: Jeppe T
authors.initials: JT
authors.lastname: Pedersen
authors.affiliation: Department of Biology, University of Copenhagen, Ole Maaløesvej 5, 2200 Copenhagen (Denmark).
authors.forename: Christian B
authors.initials: CB
authors.lastname: Borg
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK).
authors.forename: Thomas C T
authors.initials: TC
authors.lastname: Michaels
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK).
authors.forename: Tuomas P J
authors.initials: TP
authors.lastname: Knowles
authors.affiliation: Université de Toulouse; UPS, INPT 31077 Toulouse (France) and LCC (Laboratoire de Chimie de Coordination), CNRS UPR 8241 205, Route de Narbonne, 31077 Toulouse Cedex 4 (France).
authors.forename: Peter
authors.initials: P
authors.lastname: Faller
authors.affiliation: Department of Biology, University of Copenhagen, Ole Maaløesvej 5, 2200 Copenhagen (Denmark).
authors.forename: Kaare
authors.initials: K
authors.lastname: Teilum
authors.affiliation: Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen (Denmark). lhe@chem.ku.dk.
authors.forename: Lars
authors.initials: L
authors.lastname: Hemmingsen
mesh_terms: D000138:Acidosis / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D066329:Protein Aggregates; D003300:Copper
keywords: NMR spectroscopy; amyloid beta-peptides; copper; kinetics; stopped-flow