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

Ann Tiiman, Jinghui Luo, Cecilia Wallin, Lisa Olsson, Joel Lindgren, Jüri Jarvet, Roos Per, Sabrina B. Sholts, Shai Rahimipour, Jan Pieter Abrahams, Amelie Eriksson Karlström, Astrid Gräslund, Sebastian K.T.S. Wärmländer

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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 Z Aβ3 (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 K D 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.

Original languageEnglish
Pages (from-to)971-982
Number of pages12
JournalJournal of Alzheimer's Disease
Volume54
Issue number3
DOIs
StatePublished - 2016

Bibliographical note

Publisher Copyright:
© 2016-IOS Press and the authors. All rights reserved.

Keywords

  • Alzheimer's disease
  • copper-binding protein
  • hydrogen peroxide
  • membrane chemistry
  • neurodegeneration
  • protein aggregation

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