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Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. AD brains display deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-β (Aβ) peptides, and Aβ oligomers are likely a toxic species in AD pathology. AD patients display altered metal homeostasis, and AD...

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Autores principales: Berntsson, Elina, Vosough, Faraz, Svantesson, Teodor, Pansieri, Jonathan, Iashchishyn, Igor A., Ostojić, Lucija, Dong, Xiaolin, Paul, Suman, Jarvet, Jüri, Roos, Per M., Barth, Andreas, Morozova-Roche, Ludmilla A., Gräslund, Astrid, Wärmländer, Sebastian K. T. S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9971182/
https://www.ncbi.nlm.nih.gov/pubmed/36849796
http://dx.doi.org/10.1038/s41598-023-29901-5
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author Berntsson, Elina
Vosough, Faraz
Svantesson, Teodor
Pansieri, Jonathan
Iashchishyn, Igor A.
Ostojić, Lucija
Dong, Xiaolin
Paul, Suman
Jarvet, Jüri
Roos, Per M.
Barth, Andreas
Morozova-Roche, Ludmilla A.
Gräslund, Astrid
Wärmländer, Sebastian K. T. S.
author_facet Berntsson, Elina
Vosough, Faraz
Svantesson, Teodor
Pansieri, Jonathan
Iashchishyn, Igor A.
Ostojić, Lucija
Dong, Xiaolin
Paul, Suman
Jarvet, Jüri
Roos, Per M.
Barth, Andreas
Morozova-Roche, Ludmilla A.
Gräslund, Astrid
Wärmländer, Sebastian K. T. S.
author_sort Berntsson, Elina
collection PubMed
description Alzheimer’s disease (AD) is the most common cause of dementia worldwide. AD brains display deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-β (Aβ) peptides, and Aβ oligomers are likely a toxic species in AD pathology. AD patients display altered metal homeostasis, and AD plaques show elevated concentrations of metals such as Cu, Fe, and Zn. Yet, the metal chemistry in AD pathology remains unclear. Ni(II) ions are known to interact with Aβ peptides, but the nature and effects of such interactions are unknown. Here, we use numerous biophysical methods—mainly spectroscopy and imaging techniques—to characterize Aβ/Ni(II) interactions in vitro, for different Aβ variants: Aβ(1–40), Aβ(1–40)(H6A, H13A, H14A), Aβ(4–40), and Aβ(1–42). We show for the first time that Ni(II) ions display specific binding to the N-terminal segment of full-length Aβ monomers. Equimolar amounts of Ni(II) ions retard Aβ aggregation and direct it towards non-structured aggregates. The His6, His13, and His14 residues are implicated as binding ligands, and the Ni(II)·Aβ binding affinity is in the low µM range. The redox-active Ni(II) ions induce formation of dityrosine cross-links via redox chemistry, thereby creating covalent Aβ dimers. In aqueous buffer Ni(II) ions promote formation of beta sheet structure in Aβ monomers, while in a membrane-mimicking environment (SDS micelles) coil–coil helix interactions appear to be induced. For SDS-stabilized Aβ oligomers, Ni(II) ions direct the oligomers towards larger sizes and more diverse (heterogeneous) populations. All of these structural rearrangements may be relevant for the Aβ aggregation processes that are involved in AD brain pathology.
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spelling pubmed-99711822023-03-01 Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides Berntsson, Elina Vosough, Faraz Svantesson, Teodor Pansieri, Jonathan Iashchishyn, Igor A. Ostojić, Lucija Dong, Xiaolin Paul, Suman Jarvet, Jüri Roos, Per M. Barth, Andreas Morozova-Roche, Ludmilla A. Gräslund, Astrid Wärmländer, Sebastian K. T. S. Sci Rep Article Alzheimer’s disease (AD) is the most common cause of dementia worldwide. AD brains display deposits of insoluble amyloid plaques consisting mainly of aggregated amyloid-β (Aβ) peptides, and Aβ oligomers are likely a toxic species in AD pathology. AD patients display altered metal homeostasis, and AD plaques show elevated concentrations of metals such as Cu, Fe, and Zn. Yet, the metal chemistry in AD pathology remains unclear. Ni(II) ions are known to interact with Aβ peptides, but the nature and effects of such interactions are unknown. Here, we use numerous biophysical methods—mainly spectroscopy and imaging techniques—to characterize Aβ/Ni(II) interactions in vitro, for different Aβ variants: Aβ(1–40), Aβ(1–40)(H6A, H13A, H14A), Aβ(4–40), and Aβ(1–42). We show for the first time that Ni(II) ions display specific binding to the N-terminal segment of full-length Aβ monomers. Equimolar amounts of Ni(II) ions retard Aβ aggregation and direct it towards non-structured aggregates. The His6, His13, and His14 residues are implicated as binding ligands, and the Ni(II)·Aβ binding affinity is in the low µM range. The redox-active Ni(II) ions induce formation of dityrosine cross-links via redox chemistry, thereby creating covalent Aβ dimers. In aqueous buffer Ni(II) ions promote formation of beta sheet structure in Aβ monomers, while in a membrane-mimicking environment (SDS micelles) coil–coil helix interactions appear to be induced. For SDS-stabilized Aβ oligomers, Ni(II) ions direct the oligomers towards larger sizes and more diverse (heterogeneous) populations. All of these structural rearrangements may be relevant for the Aβ aggregation processes that are involved in AD brain pathology. Nature Publishing Group UK 2023-02-27 /pmc/articles/PMC9971182/ /pubmed/36849796 http://dx.doi.org/10.1038/s41598-023-29901-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Berntsson, Elina
Vosough, Faraz
Svantesson, Teodor
Pansieri, Jonathan
Iashchishyn, Igor A.
Ostojić, Lucija
Dong, Xiaolin
Paul, Suman
Jarvet, Jüri
Roos, Per M.
Barth, Andreas
Morozova-Roche, Ludmilla A.
Gräslund, Astrid
Wärmländer, Sebastian K. T. S.
Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides
title Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides
title_full Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides
title_fullStr Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides
title_full_unstemmed Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides
title_short Residue-specific binding of Ni(II) ions influences the structure and aggregation of amyloid beta (Aβ) peptides
title_sort residue-specific binding of ni(ii) ions influences the structure and aggregation of amyloid beta (aβ) peptides
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9971182/
https://www.ncbi.nlm.nih.gov/pubmed/36849796
http://dx.doi.org/10.1038/s41598-023-29901-5
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