Free Superoxide is an Intermediate in the Production of H₂O₂ by Copper(I)‐Aβ Peptide and O₂

Abstract

Oxidative stress is considered as an important factor and an early event in the etiology of Alzheimer's disease (AD). Cu bound to the peptide amyloid-β (Aβ) is found in AD brains, and Cu-Aβ could contribute to this oxidative stress, as it is able to produce in vitro H2O2 and HO˙ in the presence of oxygen and biological reducing agents such as ascorbate. The mechanism of Cu-Aβ-catalyzed H2O2 production is however not known, although it was proposed that H2O2 is directly formed from O2 via a 2-electron process. Here, we implement an electrochemical setup and use the specificity of superoxide dismutase-1 (SOD1) to show, for the first time, that H2O2 production by Cu-Aβ in the presence of ascorbate occurs mainly via a free O2˙(-) intermediate. This finding radically changes the view on the catalytic mechanism of H2O2 production by Cu-Aβ, and opens the possibility that Cu-Aβ-catalyzed O2˙(-) contributes to oxidative stress in AD, and hence may be of interest.

The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease

“…In vitro evidence for the ability of Aβ 1−x to generate ROS in the presence of Cu 2+ and biological reducing agents was quickly established (Huang et al, 1999; Opazo et al, 2002) although continues to be debated (Mayes et al, 2014; Pedersen et al, 2016; Reybier et al, 2016), while the underlying coordination chemistry has largely been unraveled (Drew and Barnham, 2011; Faller et al, 2014). A greater degree of H 2 O 2 production was reported for Cu 2+ and Fe 3+ in the presence of human Aβ 1−x vs. rat/mouse Aβ 1−x (Huang et al, 1999; Barnham et al, 2003a), which was concluded to be consistent with an absence of amyloid pathology in these animals.…”

“…From the perspective of the bioinorganic chemist, the past decade has led to a reasonable consensus regarding the coordination chemistry, thermodynamic stability and in vitro mechanism of ROS production by copper and Aβ (Drew and Barnham, 2011; Faller et al, 2014; Reybier et al, 2016). Despite this detailed knowledge, no therapeutic has been designed that specifically takes advantage of this structural information, although a large number of chelators and oligopeptides have been proposed (reviewed in Telpoukhovskaia and Orvig, 2013).…”

Towards High‐Throughput Modelling of Copper Reactivity Induced by Structural Disorder in Amyloid Peptides

“…[1,2] This activation has been addressed as an important pathway for triggering cell death in neurodegeneration, [3][4][5] and modelsf or dioxygen activation have been proposed on the basis of calculations. [1,2] This activation has been addressed as an important pathway for triggering cell death in neurodegeneration, [3][4][5] and modelsf or dioxygen activation have been proposed on the basis of calculations.…”

“…[18] Production of ROS by Cu-Ab 42 is comparablet o that of Cu II -(Gly-His-Lys) (Cu-GHK), an aturallyo ccurring Cu complex involved in many biochemical pathways. [22] ReactionM echanism According to recente xperimental results, [1] the first step in ROS production catalysed by Cu-Ab is the in situ production of superoxide. This coordination strongly disfavours any transientC u I -DAHK formation,c ontrary to the case of Cu-GHK.…”

“…[1] The first step is the production of the smalla mount of Cu I -Ab complex [1] The first step is the production of the smalla mount of Cu I -Ab complex…”