title: Specific Binding of Cu(II) Ions to Amyloid-Beta Peptides Bound to Aggregation-Inhibiting Molecules or SDS Micelles Creates Complexes that Generate Radical Oxygen Species.
abstract: Aggregation of the amyloid-beta (Aβ) peptide into insoluble plaques is a major factor in Alzheimer's disease (AD) pathology. Another major factor in AD is arguably metal ions, as metal dyshomeostasis is observed in AD patients, metal ions modulate Aβ aggregation, and AD plaques contain numerous metals including redox-active Cu and Fe ions. In vivo, Aβ is found in various cellular locations including membranes. So far, Cu(II)/Aβ interactions and ROS generation have not been investigated in a membrane environment. Here, we study Cu(II) and Zn(II) interactions with Aβ bound to SDS micelles or to engineered aggregation-inhibiting molecules (the cyclic peptide CP-2 and the ZAβ3(12-58)Y18L Affibody molecule). In all studied systems the Aβ N-terminal segment was found to be unbound, unstructured, and free to bind metal ions. In SDS micelles, Aβ was found to bind Cu(II) and Zn(II) with the same ligands and the same KD as in aqueous solution. ROS was generated in all Cu(II)/Aβ complexes. These results indicate that binding of Aβ to membranes, drugs, and other entities that do not interact with the Aβ N-terminal part, appears not to compromise the N-terminal segment's ability to bind metal ions, nor impede the capacity of N-terminally bound Cu(II) to generate ROS.
authors: Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Sweden.
authors: Ann
authors: A
authors: Tiiman
authors: Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Sweden.|Chemical Research Laboratory, University of Oxford, UK.
authors: Jinghui
authors: J
authors: Luo
authors: Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Sweden.
authors: Cecilia
authors: C
authors: Wallin
authors: Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Sweden.
authors: Lisa
authors: L
authors: Olsson
authors: Affibody AB, Solna, Sweden.
authors: Joel
authors: J
authors: Lindgren
authors: Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Sweden.|The National Institute of Chemical Physics and Biophysics, Tallinn, Estonia.
authors: Jϋri
authors: J
authors: Jarvet
authors: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Physiology, Capio St.Göran Hospital, Stockholm, Sweden.
authors: Roos
authors: R
authors: Per
authors: Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Sweden.|Department of Anthropology, National Museum of Natural History, Smithsonian Institution, Washington, DC, USA.
authors: Sabrina B
authors: SB
authors: Sholts
authors: Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel.
authors: Shai
authors: S
authors: Rahimipour
authors: Biozentrum, University of Basel, Switzerland & Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
authors: Jan Pieter
authors: JP
authors: Abrahams
authors: School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors: Amelie Eriksson
authors: AE
authors: Karlström
authors: Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Sweden.
authors: Astrid
authors: A
authors: Gräslund
authors: Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, Sweden.
authors: Sebastian K T S
authors: SK
authors: Wärmländer
mesh_terms: D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D003300:Copper / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008823:Micelles; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism*; D066329:Protein Aggregates / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D008823:Micelles; D010446:Peptide Fragments; D066329:Protein Aggregates; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); D003300:Copper; D006861:Hydrogen Peroxide
keywords: Alzheimer’s disease; copper-binding protein; hydrogen peroxide; membrane 
  chemistry; neurodegeneration; protein aggregation