Redox chemistry of copper-amyloid-beta: the generation of hydroxyl radical in the presence of ascorbate is linked to redox-potentials and aggregation state.
Aggregation of the beta-amyloid peptide (Abeta) to amyloid plaques is a key event in Alzheimer's disease. According to the amyloid-cascade hypothesis, Abeta 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 Abeta and influence its aggregation properties. Moreover, Cu-Abeta is supposed to be directly involved in ROS production. To get a better understanding of these reactions, we measured the production of HO(.) and the redox potential of Cu-Abeta. The results were compared to other biological copper-peptide complexes in order to get an insight into the biological relevance. Cu-Abeta produced more HO(.) than the complex of copper with Asp-Ala-His-Lys (Cu-DAHK), but less than with Gly-His-Lys (Cu-GHK). Cyclic voltammetry revealed that the order for reduction potential is Cu-GHK>Cu-Abeta>Cu-DAHK, but for the oxidation potential the order is reversed. Thus, easier copper redox cycling correlated to higher HO(.) production. The copper complex of the form Abeta1-42 showed a HO(.) production five-times higher than that of the form Abeta1-40. Time-dependence and aggregation studies suggest that an aggregation intermediate is responsible for this increased HO(.) production.
Guilloreau
Luc
L
Laboratoire de Chimie de Coordination, CNRS UPR 8241 associated with the University of Toulouse III, 205 route de Narbonne, 31077 Toulouse Cedex 4, France.
Combalbert
Sarah
S
Sournia-Saquet
Alix
A
Mazarguil
Honoré
H
Faller
Peter
P
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D001205:Ascorbic Acid / Q000737:chemistry* / Q000378:metabolism; D003300:Copper / Q000737:chemistry* / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D017665:Hydroxyl Radical / Q000737:chemistry* / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction
D016229:Amyloid beta-Peptides; D017665:Hydroxyl Radical; D003300:Copper; D001205:Ascorbic Acid