Electrochemical and homogeneous electron transfers to the Alzheimer amyloid-beta copper complex follow a preorganization mechanism

Abstract

Deciphering the electron transfer reactivity characteristics of amyloid β-peptide copper complexes is an important task in connection with the role they are assumed to play in Alzheimer's disease. A systematic analysis of this question with the example of the amyloid β-peptide copper complex by means of its electrochemical current-potential responses and of its homogenous reactions with electrogenerated fast electron exchanging osmium complexes revealed a quite peculiar mechanism: The reaction proceeds through a small fraction of the complex molecules in which the peptide complex is "preorganized" so as the distances and angles in the coordination sphere to vary minimally upon electron transfer, thus involving a remarkably small reorganization energy (0.3 eV). This preorganization mechanism and its consequences on the reactivity should be taken into account for reactions involving dioxygen and hydrogen peroxide that are considered to be important in Alzheimer's disease through the production of harmful reactive oxygen species.

Fig. 1.

Cyclic voltammetric responses, at a glassy carbon electrode, of a 0.2-mM solution of Cu^II in a 25-mM pipes buffer of pH = 6.7 in the presence of 0.2 M KCl as a function of successive addition of the Aβ16 peptide of (from top to bottom) 0, 0.1, 0.2, 0.3 (A), 0.3, 0.4, 0.5, 0.6, 0.8 (B), and 1, 2, 3, 4, 5 (C) equivalents. Scan rate: 0.02 V/s. The background current has been subtracted in all cases. Temperature: 20 °C.

Fig. 2.

Gray curves: cyclic voltammetric responses (corrected from the background current), at a glassy carbon electrode, of a 0.2-mM solution of Cu^II in a 25-mM pipes buffer of pH = 6.7 in the presence of 0.2 M KCl after addition of 1 mM Aβ16 peptide, as a function of the scan rate (v). Black curve: simulated current-potential curve according to the preorganization mechanism (third mechanism in Scheme 1); for details and parameter values, see Section 2.6. (Top Left) Diagram illustrates the way in which the background signal (dotted line) has been subtracted from the raw cyclic voltammogram (light gray curve) to obtain the corrected response (gray curve). Temperature: 20 °C.

Scheme 1.

Reactions schemes

Fig. 3.

Thick gray curves: cyclic voltammetric responses (corrected from the background current), at a glassy carbon electrode, of a 0.2-mM solution of Cu^II in a pipes buffer of pH = 6.7 in the presence of 0.2 M KCl after addition of 1 mM Aβ16 peptide. Scan rate: 0.02 V/s. (A) Thin curves: simulated current-potential curve according to a simple electron transfer mechanism (first mechanism in Scheme 1, section 2.4) obeying the MHL law with E⁰ = 0.17 V vs. NHE and D_Cu(Aβ) = 2 × 10^-6 cm² s^-1. Solid curve: λ = 1.4 eV, Z = 18 cm s^-1, dotted curve: λ = 0.3 eV, Z = 5 × 10^-3 cm s^-1; (B) thin curve simulation according to the square scheme mechanism (Scheme 1, section 2.5).

Fig. 4.

Catalytic cyclic voltammetric responses, at a glassy carbon electrode, of a 0.2-mM solution of Cu^II in a pH = 6.7 pipes buffer containing 0.2 M KCl in the presence of 1-mM solution of Aβ16 and of 0.02 mM [Os^III(bpy)₂(py)Cl](PF₆)₂ (A) and [Os^III(dmbpy)₂Cl₂](PF₆) (B). Dotted line: Os mediator alone; dashed line: Cu(Aβ) alone; thick gray line: mediator and Cu(Aβ) together; solid black line: simulation of redox catalytic response (see text). Scan rate: 0.02 V/s.

Scheme 2.

Indirect electrochemistry of the Cu^II/I(Aβ) couple by means of an Os^III/II couple