Iron Complexation Research Papers - Academia.edu (original) (raw)

"Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder characterized by the deposition of amyloid plaque. The plaque is primarily composed of insoluble beta-amyloid (Aβ) peptide fibrils and elevated metal concentrations, namely copper, iron, and zinc. In a human brain, the neurotoxicity of the plaque has been linked to a Fenton-like reaction wherein the Aβ-metal complex(es) is(are) involved in the generation of reactive oxygen species (ROS), such as hydrogen peroxide and possibly hydroxyl radicals, which are believed to be responsible for the oxidative stress that forms in an AD-affected brain. To date, the majority of studies have focused on Aβ-copper interactions, and to a lesser degree, Aβ-zinc, but Aβ-iron complexes have yet to be studied in detail. As such, the objective of this research is to determine whether an in vitro Aβ-Fe complex can form, and if so, can it facilitate the production of hydrogen peroxide.

Matrix assisted laser desorption/ionization quadrupole time-of-flight mass spectrometry and fluorescence spectroscopy confirmed the formation of a significant amount of Aβ-Fe complex in the presence of Fe3+ but not Fe2+. Additionally, the equilibrium for the reaction (Kd = 4.499 x 10-4 M and Kb = 0.223 x 104 M-1) was found to favor the reactants, although, hydrolysis may have greatly affected these findings.

When a potential was applied to the complex, the resulting reversible cyclic voltammogram (Delta Ep ~ 60mV) suggests that the complex is redox-active, and thermodynamically capable of reducing O2 to H2O2 (E o ~ 0.48 V vs. Ag/AgCl) based on a calculated formal potential of ~ 0.195 V vs. Ag/AgCl, which is being reported for the first time. However, this reaction was not detected given the reduction wave of oxygen by the complex was not observed. This may be due to fouling of the electrode surface by the hydrolyzed Fe3+ product and/or the kinetically unfavored nature of the reaction given the time frame of the CV experiment. Further study employing other techniques are need to better discern whether this reaction does in fact proceed.

Lastly, when the complex was exposed to excess amounts of 1,10-phenanthroline, a chelating Fe2+ indicator, the absence of a ferrion induced UV-vis absorption band at ~ 530 nm implies that the oxidation state of the complexed iron is 3+.

Taken together, these data present strong evidence for the in vitro complexation of A and Fe3+ to form a redox-active species, Aβ-Fe3+. This species does not appear to participate in the Fenton-like redox cycling of the complexed iron and reduction of oxygen to produce hydrogen peroxide, as previously proposed by Bush and coworkers [Huang, X., et al. (1999) Biochemistry 38, 7609-7616]. However, given the existence of antioxidants in the brain, such as ascorbic acid, which are capable of reducing the Aβ-Fe3+,complex to Aβ-Fe2+, the catalytic reduction of oxygen by Aβ-Fe2+ to produce ROS may be possible."