Three Histidine Residues of Amyloid-β Peptide Control the Redox Activity of Copper and Iron

Abstract

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.

Nucleic acid oxidation in Alzheimer disease

“…Interestingly, the levels of 8OHG are inversely related to the amount of amyloid-β present as extracellular deposits [10] or intracellular oligomeric forms [58], suggesting a complex interplay between amyloid-β and redox metal activity that may be critical to metal dynamics within the neuronal cytoplasm [59,60]. A possible key element in these dynamics is mitochondria in the neuronal cell body.…”

Thermodynamic study of Cu2+ binding to the DAHK and GHK peptides by isothermal titration calorimetry (ITC) with the weaker competitor glycine

“…This tripeptide also actively participates in the processes of wound healing and tissue repair [16]. It was also reported to compete successfully with Aβ for Cu 2+ coordination, thus being able to act as a potential protector from Cu-Aβ toxicity [12,15,18].…”

Copper in Alzheimer’s disease: Implications in amyloid aggregation and neurotoxicity

“…70 Based on these results, Nakamura et al have proposed that the His6, His13, and His14 residues of Aβ 42 control the redox activity of transition metals present in senile plaques. 73 Other recent studies suggest that apart from His13 and His14, Asp1 is the other main ligand in the most redox-active site that efficiently allow the oxidation of copper by H 2 O 2 and its reduction by ascorbate. 74 As the ligand sphere is different from the main Cu(II)-Aβ and Cu(I)-Aβ coordination spheres, it has been identified as an in-between state, which is only sparsely populated (0.1%).…”