Redox chemistry of copper-amyloid-β:: The generation of hydroxyl radical in the presence of ascorbate is linked to redox-potentials and aggregation state

Aggregation of the beta-amyloid peptide (A beta) to amyloid plaques is a key event in Alzheimer's disease. According to the amyloid-cascade hypothesis, A beta aggregates are toxic to neurons through the production of reactive oxygen species (ROS). Copper ions play an important role, because they are able to bind to A beta and influence its aggregation properties. Moreover, Cu-A beta is supposed to be directly involved in ROS production. To get a better understanding of these reactions, we measured the production of HO center dot and the redox potential of Cu-A beta. The results were compared to other biological copper-peptide complexes in order to get an insight into the biological relevance. Cu-A beta produced more HO center dot than the complex of copper with Asp-Ala-His-Lys (Cu-DAHK), but less than with Gly-His-Lys (Cu-GHK). Cyclic voltommetry revealed that the order for reduction potential is Cu-GHK > Cu-Ap > Cu-DAHK, but for the oxidation potential the order is reversed. Thus, easier copper redox cycling correlated to higher HO center dot production. The copper complex of the form A beta 1-42 showed a HID center dot production five-times higher than that of the form A beta 1-40. Time-dependence and aggregation studies suggest that an aggregation intermediate is responsible for this increased HO center dot production.