title: Characterization of Mn(II) ion binding to the amyloid-β peptide in Alzheimer's disease.
abstract: Growing evidence links neurodegenerative diseases to metal exposure. Aberrant metal ion concentrations have been noted in Alzheimer's disease (AD) brains, yet the role of metals in AD pathogenesis remains unresolved. A major factor in AD pathogenesis is considered to be aggregation of and amyloid formation by amyloid-β (Aβ) peptides. Previous studies have shown that Aβ displays specific binding to Cu(II) and Zn(II) ions, and such binding has been shown to modulate Aβ aggregation. Here, we use nuclear magnetic resonance (NMR) spectroscopy to show that Mn(II) ions also bind to the N-terminal part of the Aβ(1-40) peptide, with a weak binding affinity in the milli- to micromolar range. Circular dichroism (CD) spectroscopy, solid state atomic force microscopy (AFM), fluorescence spectroscopy, and molecular modeling suggest that the weak binding of Mn(II) to Aβ may not have a large effect on the peptide's aggregation into amyloid fibrils. However, identification of an additional metal ion displaying Aβ binding reveals more complex AD metal chemistry than has been previously considered in the literature.
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius väg 16C, 106 91 Stockholm, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Wallin
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, Husargatan 3, 751 24 Uppsala, Sweden.
authors.forename: Yashraj S
authors.initials: YS
authors.lastname: Kulkarni
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius väg 16C, 106 91 Stockholm, Sweden; Department of Neurobiology, Care Sciences and Society (NVS), H1, Division of Neurogeriatrics, Karolinska Institutet, Novum Pl 5 14157 Huddinge, Stockholm, Sweden.
authors.forename: Axel
authors.initials: A
authors.lastname: Abelein
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius väg 16C, 106 91 Stockholm, Sweden; The National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia​.
authors.forename: Jüri
authors.initials: J
authors.lastname: Jarvet
authors.affiliation: Institute of Complex Systems: Structural Biochemistry, Forschungszentrum Jülich, Jülich, 52425, Germany.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Liao
authors.affiliation: Institute of Complex Systems: Structural Biochemistry, Forschungszentrum Jülich, Jülich, 52425, Germany; Institute of Theoretical and Computational Chemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Strodel
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius väg 16C, 106 91 Stockholm, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Olsson
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius väg 16C, 106 91 Stockholm, Sweden; Chemical Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Luo
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland; Laboratory of Biomolecular Research, Paul Scherrer Institute, Department of Biology and Chemistry, OFLC/102CH-5232 Villigen PSI, Switzerland.
authors.forename: Jan Pieter
authors.initials: JP
authors.lastname: Abrahams
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius väg 16C, 106 91 Stockholm, Sweden; Department of Anthropology, National Museum of Natural History, Smithsonian Institution, 10th and Constitution Avenue NW, Washington, DC 20013, USA.
authors.forename: Sabrina B
authors.initials: SB
authors.lastname: Sholts
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Nobels väg 13, 171 77 Stockholm, Sweden; Department of Clinical Physiology, Capio St.Göran Hospital, St.Göransplan 1, 112 19 Stockholm, Sweden.
authors.forename: Per M
authors.initials: PM
authors.lastname: Roos
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, Husargatan 3, 751 24 Uppsala, Sweden.
authors.forename: Shina C L
authors.initials: SC
authors.lastname: Kamerlin
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius väg 16C, 106 91 Stockholm, Sweden.
authors.forename: Astrid
authors.initials: A
authors.lastname: Gräslund
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius väg 16C, 106 91 Stockholm, Sweden. Electronic address: seb@dbb.su.se.
authors.forename: Sebastian K T S
authors.initials: SK
authors.lastname: Wärmländer
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D006801:Humans; D007477:Ions / Q000737:chemistry / Q000378:metabolism; D008345:Manganese / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D007477:Ions; D008345:Manganese
keywords: Manganese; Metal-protein binding; Molecular dynamics; Neurodegeneration; Spectroscopy