Redox-Dependent Copper Ion Modulation of Amyloid-β (1-42) Aggregation In Vitro
| Autor: | István T. Horváth, David Bernson, Elin K. Esbjörner, Nima Sasanian, Pernilla Wittung-Stafshede |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Amyloid Kinetics lcsh:QR1-502 chemistry.chemical_element amyloid-β 010402 general chemistry Fibril 01 natural sciences Biochemistry Redox Article lcsh:Microbiology Ion Protein Aggregates 03 medical and health sciences Ion binding mental disorders Molecular Biology Ions Amyloid beta-Peptides Chemistry aggregation amyloid Hydrogen-Ion Concentration Copper Peptide Fragments Recombinant Proteins In vitro inhibition 0104 chemical sciences 030104 developmental biology kinetics copper Biophysics Oxidation-Reduction Alzheimer’s disease |
| Zdroj: | Biomolecules, Vol 10, Iss 924, p 924 (2020) Biomolecules Volume 10 Issue 6 |
| Popis: | Plaque deposits composed of amyloid-&beta (A&beta ) fibrils are pathological hallmarks of Alzheimer&rsquo s disease (AD). Although copper ion dyshomeostasis is apparent in AD brains and copper ions are found co-deposited with A&beta peptides in patients&rsquo plaques, the molecular effects of copper ion interactions and redox-state dependence on A&beta aggregation remain elusive. By combining biophysical and theoretical approaches, we here show that Cu2+ (oxidized) and Cu+ (reduced) ions have opposite effects on the assembly kinetics of recombinant A&beta (1-42) into amyloid fibrils in vitro. Cu2+ inhibits both the unseeded and seeded aggregation of A&beta (1-42) at pH 8.0. Using mathematical models to fit the kinetic data, we find that Cu2+ prevents fibril elongation. The Cu2+-mediated inhibition of A&beta 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 Cu2+, Cu+ ion binding mildly catalyzes the A&beta (1-42) aggregation via a mechanism that accelerates primary nucleation, possibly via the formation of Cu+-bridged A&beta (1-42) dimers. Taken together, our study emphasizes redox-dependent copper ion effects on A&beta (1-42) aggregation and thereby provides further knowledge of putative copper-dependent mechanisms resulting in AD. |
| Databáze: | OpenAIRE |
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