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

Abstract

The interaction of amyloid-β (Aβ) and redox-active metals, two important biomarkers present in the senile plaques of AD brain, has been suggested to either enhance the Aβ aggregation or facilitate the generation of reactive oxygen species (ROS). The present study investigates the nature of the interaction between the metal-binding domain of Aβ, viz,, 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 were deduced to be 6.3 × 10 -21 M 2 and 5.0 × 10 -12 M 2 , respectively, via measuring the fluorescence quenching of the sole tyrosine residue on Aβ upon the complex formation. 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 vs. 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 occurrence of a range of redox reactions with cellular species. Aβ-Fe(II)-NTA electrogenerated from Aβ-Fe(III)-NTA was also found to catalyze the reduction of oxygen to produce H 2 O 2 . 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 where 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 ROS is continuously produced, but also oxygen and biological reductants can 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 protein. Particularly, its strong affinity to Fe(II), which is eight orders of magnitude stronger than transferrin, would greatly interfere with the iron homeostasis.A major hallmark of Alzheimer's disease (AD) is the deposition of aggregates of amyloid-β (Aβ) peptides in the senile plaques.(1) The in vivo aggregation/deposition of Aβ peptides is suggested to either enhance neurotoxicity or be a result of aberrant cellular processes.(2) The

Protein Oxidation in Aging: Does It Play a Role in Aging Progression?

“…Especially the fact that oxidative stress is increased already in the stage of mild cognitive impairment, an early stage of dementia, may indicate a crucial role of oxidative stress during initiation and development of AD (133 (78,126), which may be converted to HO in a Fenton reaction. As mentioned earlier, in AD brains, there are increased levels of protein carbonyls and 3-NT (3,61,143), which serve as reliable markers for protein oxidation.…”

Iron, Oxidative Stress and Health

“…Also, labile iron pool (LIP) is present within cells. Most LIP is free iron bound to small organic chelators -citrate or adenosine phosphate, carboxylate, polypeptides, (Kohgr et al, 2008;Jiang et al, 2009). LIP is biologically active in intracellular metabolism but toxic if present in excess.…”

“…Further, A may accumulate iron from the LIP. The implications of this in generating oxidative stress need further study (Jiang et al, 2009). In animal models increased iron worsened the course of increased risk of developing the disease.…”

Structural and Computational Studies of Interactions of Metals with Amyloid Beta

“…The easy oxidation of Fe(II) to Fe(III) and the hydrolysis and precipitation of www.intechopen.com Fe(III) at physiological pH are some of the reasons hindering experimental studies. To get around the latter problem, Jiang et al (2009) used the complex between Fe(III) and nitrilotriacetic acid (NTA) in their work on the interaction with and redox properties. They found that Fe(III)-NTA bound to extremely strongly, with a measured dissociation constant of 6.3x10 -21 M. In comparison, that for Fe(II)-NTA was 5.0x10 -12 M. Furthermore, using cyclic voltametry they determined that the redox potential for Fe(II)-NTA to be 0.23 V when complexed to .…”