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

Plaque deposits composed of amyloid-ß (Aß) 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 Aß peptides in patients' plaques, the molecular effects of copper ion interactions and redox-state dependence on Aß 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 Aß(1-42) into amyloid fibrils in vitro. Cu2+ inhibits both the unseeded and seeded aggregation of Aß(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 Aß 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 Aß(1-42) aggregation via a mechanism that accelerates primary nucleation, possibly via the formation of Cu+-bridged Aß(1-42) dimers. Taken together, our study emphasizes redox-dependent copper ion effects on Aß(1-42) aggregation and thereby provides further knowledge of putative copper-dependent mechanisms resulting in AD.