A catalytic antioxidant for limiting amyloid-beta peptide aggregation and reactive oxygen species generation

Abstract

Alzheimer's disease (AD) is a multifaceted disease that is characterized by increased oxidative stress, metal-ion dysregulation, and the formation of intracellular neurofibrillary tangles and extracellular amyloid-β (Aβ) aggregates. In this work we report the large affinity binding of the iron(iii) 2,17-bis-sulfonato-5,10,15-tris(pentafluorophenyl)corrole complex <b>FeL1</b> to the Aβ peptide (<i>K</i> _d ∼ 10^-7) and the ability of the bound <b>FeL1</b> to act as a catalytic antioxidant in both the presence and absence of Cu(ii) ions. Specific findings are that: (a) an Aβ histidine residue binds axially to <b>FeL1</b>; (b) that the resulting adduct is an efficient catalase; (c) this interaction restricts the formation of high molecular weight peptide aggregates. UV-Vis and electron paramagnetic resonance (EPR) studies show that although the binding of <b>FeL1</b> does not influence the Aβ-Cu(ii) interaction (<i>K</i> _d ∼ 10^-10), bound <b>FeL1</b> still acts as an antioxidant thereby significantly limiting reactive oxygen species (ROS) generation from Aβ-Cu. Overall, <b>FeL1</b> is shown to bind to the Aβ peptide, and modulate peptide aggregation. In addition, <b>FeL1</b> forms a ternary species with Aβ-Cu(ii) and impedes ROS generation, thus showing the promise of discrete metal complexes to limit the toxicity pathways of the Aβ peptide.