Redox-Dependent Copper Ion Modulation of Amyloid-β (1-42) Aggregation In Vitro
Journal article, 2020

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.

Alzheimer’s disease

inhibition

aggregation

amyloid

copper

kinetics

amyloid-β

Author

Nima Sasanian

Chalmers, Biology and Biological Engineering, Chemical Biology

David Bernson

Chalmers, Biology and Biological Engineering, Chemical Biology

Istvan Horvath

Chalmers, Biology and Biological Engineering, Chemical Biology

Pernilla Wittung Stafshede

Chalmers, Biology and Biological Engineering, Chemical Biology

Elin Esbjörner Winters

Chalmers, Biology and Biological Engineering, Chemical Biology

Biomolecules

2218-273X (eISSN)

Vol. 10 6 1-19 924

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Subject Categories

Biological Sciences

DOI

10.3390/biom10060924

PubMed

32570820

More information

Latest update

9/17/2020