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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
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. University of Oxford, UK.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
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Number of Authors: 13
2016 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 54, no 3, 971-982 p.Article in journal (Refereed) Published
Abstract [en]

Aggregation of the amyloid-beta (A beta) 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 A beta aggregation, and AD plaques contain numerous metals including redox-active Cu and Fe ions. In vivo, A beta is found in various cellular locations including membranes. So far, Cu(II)/A beta interactions and ROS generation have not been investigated in a membrane environment. Here, we study Cu(II) and Zn(II) interactions with A beta bound to SDS micelles or to engineered aggregation-inhibiting molecules (the cyclic peptide CP-2 and the Z(A beta 3)(12-58) Y18L Affibody molecule). In all studied systems the A beta N-terminal segment was found to be unbound, unstructured, and free to bind metal ions. In SDS micelles, A beta was found to bind Cu(II) and Zn(II) with the same ligands and the same K-D as in aqueous solution. ROS was generated in all Cu(II)/A beta complexes. These results indicate that binding of A beta to membranes, drugs, and other entities that do not interact with the A beta 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.

Place, publisher, year, edition, pages
2016. Vol. 54, no 3, 971-982 p.
Keyword [en]
Alzheimer's disease, copper-binding protein, hydrogen peroxide, membrane chemistry, neurodegeneration, protein aggregation
National Category
Biological Sciences Neurosciences Neurology
Identifiers
URN: urn:nbn:se:su:diva-136236DOI: 10.3233/JAD-160427ISI: 000385651800012PubMedID: 27567855OAI: oai:DiVA.org:su-136236DiVA: diva2:1055266
Available from: 2016-12-12 Created: 2016-12-01 Last updated: 2016-12-12Bibliographically approved

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Tiiman, AnnWallin, CeciliaJarvet, JϋriGräslund, AstridWärmländer, Sebastian K. T. S.
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Department of Biochemistry and Biophysics
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