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

Abstract

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 Cu2+ (oxidized) and Cu+ (reduced) ions have opposite effects on the assembly kinetics of recombinant Aβ(1-42) into amyloid fibrils in vitro. Cu2+ 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 Cu2+ prevents fibril elongation. The Cu2+-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 Cu2+, 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.

• Authors: Nima Sasanian, David Bernson, Istvan Horvath, Pernilla Wittung-Stafshede, Elin K Esbjörner
• Journal: Biomolecules (Biomolecules) Vol. 10 Issue 6 (06 18 2020) ISSN: 2218-273X [Electronic] Switzerland
• PMID: 32570820 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Ions
• Peptide Fragments
• Protein Aggregates
• Recombinant Proteins
• amyloid beta-protein (1-42)
• Copper

Topics

• Amyloid beta-Peptides (antagonists & inhibitors, genetics, metabolism)
• Copper (chemistry, pharmacology)
• Hydrogen-Ion Concentration
• Ions (chemistry, pharmacology)
• Oxidation-Reduction
• Peptide Fragments (antagonists & inhibitors, genetics, metabolism)
• Protein Aggregates (drug effects)
• Recombinant Proteins (genetics, metabolism)