Three histidine residues of amyloid-beta peptide control the redox activity of copper and iron.
Zinc, iron and copper are concentrated in senile plaques of Alzheimer disease. Copper and iron catalyze the Fenton-Haber-Weiss reaction, which likely contributes to oxidative stress in neuronal cells. In this study, we found that ascorbate oxidase activity and the intensity of ascorbate radicals measured using ESR spectroscopy, generated by free Cu(II), was decreased in the presence of amyloid-beta (Abeta), the major component of senile plaques. Specifically, the ascorbate oxidase activity was strongly inhibited (85% decrease) in the presence of Abeta1-16 or Abeta1-42, whereas it was only slightly inhibited in the presence of Abeta1-12 or Abeta25-35 (<20% inhibition). Ascorbate-dependent hydroxyl radical generation by free Cu(II) decreased in the presence of Abeta in the identical order of Abeta1-42, Abeta1-16 > Abeta1-12 and was abolished in the presence of 2-fold molar excess glycylhystidyllysine (GHK). Ascorbate oxidase activity and ascorbate-dependent hydroxyl radical generation by free Fe(III) were inhibited by Abeta1-42, Abeta1-16, and Abeta1-12. Although Cu(II)-Abeta shows a significant SOD-like activity, the rate constant for the reaction of superoxide with Cu(II)-Abeta was much slower than that with SOD. Overall, our results suggest that His6, His13, and His14 residues of Abeta1-42 control the redox activity of transition metals present in senile plaques.
Nakamura
M
M
Department of Chemistry, Asahikawa Medical College, Asahikawa 078-8510, Japan. nmasao@asahikawa-med. ac.jp
Shishido
N
N
Nunomura
Akihiko
A
Smith
Mark A
MA
Perry
George
G
Hayashi
Y
Y
Nakayama
K
K
Hayashi
T
T
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000494:pharmacology / Q000502:physiology; D001205:Ascorbic Acid / Q000494:pharmacology; D003300:Copper / Q000378:metabolism*; D006639:Histidine / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017665:Hydroxyl Radical; D006639:Histidine; D003300:Copper; D006861:Hydrogen Peroxide; D007501:Iron; D001205:Ascorbic Acid