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Redox-Dependent Copper Ion Modulation of Amyloid-β (1-42) Aggregation In Vitro

Plaque deposits composed of amyloid-β (Aβ) fibrils are pathological hallmarks of Alzheimer’s disease (AD). Although copper ion dyshomeostasis is apparent in AD brains and copper ions are found co-deposited with Aβ peptides in patients’ plaques, the molecular effects of copper ion interactions and re...

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Autores principales: Sasanian, Nima, Bernson, David, Horvath, Istvan, Wittung-Stafshede, Pernilla, Esbjörner, Elin K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355640/
https://www.ncbi.nlm.nih.gov/pubmed/32570820
http://dx.doi.org/10.3390/biom10060924
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author Sasanian, Nima
Bernson, David
Horvath, Istvan
Wittung-Stafshede, Pernilla
Esbjörner, Elin K.
author_facet Sasanian, Nima
Bernson, David
Horvath, Istvan
Wittung-Stafshede, Pernilla
Esbjörner, Elin K.
author_sort Sasanian, Nima
collection PubMed
description Plaque deposits composed of amyloid-β (Aβ) fibrils are pathological hallmarks of Alzheimer’s disease (AD). Although copper ion dyshomeostasis is apparent in AD brains and copper ions are found co-deposited with Aβ peptides in patients’ plaques, the molecular effects of copper ion interactions and redox-state dependence on Aβ aggregation remain elusive. By combining biophysical and theoretical approaches, we here show that Cu(2+) (oxidized) and Cu(+) (reduced) ions have opposite effects on the assembly kinetics of recombinant Aβ(1-42) into amyloid fibrils in vitro. Cu(2+) inhibits both the unseeded and seeded aggregation of Aβ(1-42) at pH 8.0. Using mathematical models to fit the kinetic data, we find that Cu(2+) prevents fibril elongation. The Cu(2+)-mediated inhibition of Aβ aggregation shows the largest effect around pH 6.0 but is lost at pH 5.0, which corresponds to the pH in lysosomes. In contrast to Cu(2+), Cu(+) ion binding mildly catalyzes the Aβ(1-42) aggregation via a mechanism that accelerates primary nucleation, possibly via the formation of Cu(+)-bridged Aβ(1-42) dimers. Taken together, our study emphasizes redox-dependent copper ion effects on Aβ(1-42) aggregation and thereby provides further knowledge of putative copper-dependent mechanisms resulting in AD.
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spelling pubmed-73556402020-07-23 Redox-Dependent Copper Ion Modulation of Amyloid-β (1-42) Aggregation In Vitro Sasanian, Nima Bernson, David Horvath, Istvan Wittung-Stafshede, Pernilla Esbjörner, Elin K. Biomolecules Article Plaque deposits composed of amyloid-β (Aβ) fibrils are pathological hallmarks of Alzheimer’s disease (AD). Although copper ion dyshomeostasis is apparent in AD brains and copper ions are found co-deposited with Aβ peptides in patients’ plaques, the molecular effects of copper ion interactions and redox-state dependence on Aβ aggregation remain elusive. By combining biophysical and theoretical approaches, we here show that Cu(2+) (oxidized) and Cu(+) (reduced) ions have opposite effects on the assembly kinetics of recombinant Aβ(1-42) into amyloid fibrils in vitro. Cu(2+) inhibits both the unseeded and seeded aggregation of Aβ(1-42) at pH 8.0. Using mathematical models to fit the kinetic data, we find that Cu(2+) prevents fibril elongation. The Cu(2+)-mediated inhibition of Aβ aggregation shows the largest effect around pH 6.0 but is lost at pH 5.0, which corresponds to the pH in lysosomes. In contrast to Cu(2+), Cu(+) ion binding mildly catalyzes the Aβ(1-42) aggregation via a mechanism that accelerates primary nucleation, possibly via the formation of Cu(+)-bridged Aβ(1-42) dimers. Taken together, our study emphasizes redox-dependent copper ion effects on Aβ(1-42) aggregation and thereby provides further knowledge of putative copper-dependent mechanisms resulting in AD. MDPI 2020-06-18 /pmc/articles/PMC7355640/ /pubmed/32570820 http://dx.doi.org/10.3390/biom10060924 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sasanian, Nima
Bernson, David
Horvath, Istvan
Wittung-Stafshede, Pernilla
Esbjörner, Elin K.
Redox-Dependent Copper Ion Modulation of Amyloid-β (1-42) Aggregation In Vitro
title Redox-Dependent Copper Ion Modulation of Amyloid-β (1-42) Aggregation In Vitro
title_full Redox-Dependent Copper Ion Modulation of Amyloid-β (1-42) Aggregation In Vitro
title_fullStr Redox-Dependent Copper Ion Modulation of Amyloid-β (1-42) Aggregation In Vitro
title_full_unstemmed Redox-Dependent Copper Ion Modulation of Amyloid-β (1-42) Aggregation In Vitro
title_short Redox-Dependent Copper Ion Modulation of Amyloid-β (1-42) Aggregation In Vitro
title_sort redox-dependent copper ion modulation of amyloid-β (1-42) aggregation in vitro
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355640/
https://www.ncbi.nlm.nih.gov/pubmed/32570820
http://dx.doi.org/10.3390/biom10060924
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