Ternary Complexes of Iron, Amyloid-β, and Nitrilotriacetic Acid: Binding Affinities, Redox Properties, and Relevance to Iron-Induced Oxidative Stress in Alzheimer’s Disease

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• 作者：Dianlu Jiang ; Xiangjun Li ; Renee Williams ; Sveti Patel ; Lijie Men ; Yinsheng Wang ; Feimeng Zhou
• 刊名：Biochemistry
• 出版年：2009
• 出版时间：August 25, 2009
• 年：2009
• 卷：48
• 期：33
• 页码：7939-7947
• 全文大小：849K
• 年卷期：v.48,no.33(August 25, 2009)
• ISSN：1520-4995

文摘

The interaction of amyloid-β (Aβ) and redox-active metals, two important biomarkers present in the senile plaques of Alzheimer's disease (AD) brain, has been suggested to enhance the Aβ aggregation or facilitate the generation of reactive oxygen species (ROS). This study investigates the nature of the interaction between the metal-binding domain of Aβ, viz., Aβ(1−16), and the Fe(III) or Fe(II) complex with nitrilotriacetic acid (NTA). Using electrospray ionization mass spectrometry (ESI-MS), the formation of a ternary complex of Aβ(1−16), Fe(III), and NTA with a stoichiometry of 1:1:1 was identified. MS also revealed that the NTA moiety can be detached via collision-induced dissociation. The cumulative dissociation constants of both Aβ−Fe(III)−NTA and Aβ−Fe(II)−NTA complexes were deduced to be 6.3 × 10⁻²¹ and 5.0 × 10⁻¹² M², respectively, via measurement of the fluorescence quenching of the sole tyrosine residue on Aβ upon formation of the complex. The redox properties of these two complexes were investigated by cyclic voltammetry. The redox potential of the Aβ−Fe(III)−NTA complex was found to be 0.03 V versus Ag/AgCl, which is negatively shifted by 0.54 V when compared to the redox potential of free Fe(III)/Fe(II). Despite such a large potential modulation, the redox potential of the Aβ−Fe(III)−NTA complex is still sufficiently high for a range of redox reactions with cellular species to occur. The Aβ−Fe(II)−NTA complex electrogenerated from the Aβ−Fe(III)−NTA complex was also found to catalyze the reduction of oxygen to produce H₂O₂. These findings provide significant insight into the role of iron and Aβ in the development of AD. The binding of iron by Aβ modulates the redox potential to a level at which its redox cycling occurs. In the presence of a biological reductant (antioxidant), redox cycling of iron could disrupt the redox balance within the cellular milieu. As a consequence, not only is ROS continuously produced, but oxygen and biological reductants can also be depleted. A cascade of biological processes can therefore be affected. In addition, the strong binding affinity of Aβ toward Fe(III) and Fe(II) indicates Aβ could compete for iron against other iron-containing proteins. In particular, its strong affinity for Fe(II), which is 8 orders of magnitude stronger than that of transferrin, would greatly interfere with iron homeostasis.