Issue 6, 2019

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 FeL1 to the Aβ peptide (Kd ∼ 10−7) and the ability of the bound FeL1 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 FeL1; (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 FeL1 does not influence the Aβ–Cu(II) interaction (Kd ∼ 10−10), bound FeL1 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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
19 Oct 2018
Accepted
27 Nov 2018
First published
03 Dec 2018
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2019,10, 1634-1643

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

L. M. F. Gomes, A. Mahammed, K. E. Prosser, J. R. Smith, M. A. Silverman, C. J. Walsby, Z. Gross and T. Storr, Chem. Sci., 2019, 10, 1634 DOI: 10.1039/C8SC04660C

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements