A catalytic antioxidant for limiting amyloid-beta peptide aggregation and reactive oxygen species generation. Issue 6 (11th December 2018)

• Record Type: Journal Article
• Authors: Gomes, Luiza M. F.; Mahammed, Atif; Prosser, Kathleen E.; Smith, Jason R.; Silverman, Michael A.; Walsby, Charles J.; Gross, Zeev; Storr, Tim
• Is Part Of: Chemical science. Volume 10:Issue 6(2019)
• Page Start: 1634
• Page End: 1643
• Publication Date: 2018-12-11
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c8sc04660c
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : An Fe corrole is shown to bind to the amyloid-beta peptide and limit reactive oxygen species generation and peptide aggregation of relevance to Alzheimer's disease. 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 complexFeL1 to the Aβ peptide ( K d ∼ 10 −7 ) and the ability of the boundFeL1 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 toFeL1 ; (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 ofFeL1 does not influence the Aβ–Cu(ii ) interaction ( K d ∼ 10 −10 ), boundFeL1 still acts as an antioxidant thereby significantly limiting reactive oxygen species (ROS) generation from Aβ-Cu. Overall, FeL1 is shown to bind to the Aβ peptide, and modulate peptide aggregation. In addition, FeL1 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.