One- and Two-Electron Oxidations of β-Amyloid25-35 by Carbonate Radical Anion (CO3•-) and Peroxymonocarbonate (HCO4-): Role of Sulfur in Radical Reactions and Peptide Aggregation.

Mario Fontana,Alessia Baseggio Conrado,Alessandra Giorgi,Cesira Foppoli,Luciana Mosca,Simone Dinarelli,Elita Montanari,Antonio Francioso,Carla Blarzino

doi:10.3390/molecules25040961

Abstract

The β-amyloid (Aβ) peptide plays a key role in the pathogenesis of Alzheimer’s disease. The methionine (Met) residue at position 35 in Aβ C-terminal domain is critical for neurotoxicity, aggregation, and free radical formation initiated by the peptide. The role of Met in modulating toxicological properties of Aβ most likely involves an oxidative event at the sulfur atom. We therefore investigated the one- or two-electron oxidation of the Met residue of Aβ25-35 fragment and the effect of such oxidation on the behavior of the peptide. Bicarbonate promotes two-electron oxidations mediated by hydrogen peroxide after generation of peroxymonocarbonate (HCO4−, PMC). The bicarbonate/carbon dioxide pair stimulates one-electron oxidations mediated by carbonate radical anion (CO3•−). PMC efficiently oxidizes thioether sulfur of the Met residue to sulfoxide. Interestingly, such oxidation hampers the tendency of Aβ to aggregate. Conversely, CO3•− causes the one-electron oxidation of methionine residue to sulfur radical cation (MetS•+). The formation of this transient reactive intermediate during Aβ oxidation may play an important role in the process underlying amyloid neurotoxicity and free radical generation.

Highlights

Alzheimer’s disease (AD) is one of the most disabling dementia disorders among the elderly, characterized by progressive loss of memory and cognitive functions
Taking into account that the only residue susceptible to be oxidized in the fragment is the Met located at 35 position [18] and the oxidative reactions mediated by PMC proceed through a bi-electronic mechanism [22], the production of the Aβ25-35 fragment with the Met residue oxidized to methionine sulfoxide (MetSO-Aβ25-35 ) is expected
The origin of oxidative damage in AD is not yet fully understood, our experiments confirm that amyloid peptide is liable to be oxidized at level of methionine residue and that the effects of such oxidation vary depending whether one- or two-electron mechanisms are implied

Summary

Introduction

Alzheimer’s disease (AD) is one of the most disabling dementia disorders among the elderly, characterized by progressive loss of memory and cognitive functions. Molecules 2020, 25, 961 tau protein, neuronal loss, and amyloid plaques are the hallmarks of the disease [1,2]. Amyloid formation is generally associated with the AD clinical manifestations and there are many reports of Aβ peptides being toxic to neuronal cells [5,6,7]. The central role of Aβ in the pathogenesis of the disease is undisputed, the precise mechanism(s) of action and the nature of the toxic species remain to be identified [8]. The damage caused by oxidative stress may play an important role in the initiation and progression of AD. In the Aβ-associated oxidative stress model of neurodegeneration, the peptide is directly responsible for free radical-mediated damage to neuronal membrane systems, leading to subsequent neuronal loss [12,13,14].

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