Affiliations: [a] Department of Chemistry, Missouri University of Science and Technology, Rolla, MO, USA | [b] UTSA Neurosciences Institute and Department of Biology, College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA | [c] Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
Correspondence:
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Correspondence to: V. Prakash Reddy, Department of Chemistry, Missouri University of Science and Technology, Rolla, MO 65409, USA. E-mail: preddy@mst.edu.
Note: [] Handling Editor: Jesus Avila
Abstract: Amyloid-β (Aβ), the major component of senile plaques in Alzheimer's disease, is known to complex transition metal ions mainly through histidine residues. In this study, using 1H NMR titration experiments, we show that histidine binds strongly to Zn(II), Cu(II), and Fe(III) ions at a biologically relevant pH (pH 7.4), with a stoichiometry of Zn(II): histidine binding of 1:2. The observed deshielding of the chemical shifts and relative line broadening indicate that Fenton-active Cu(II) and Fe(III) bind to histidine relatively more efficiently as compared to Zn(II). Parallel studies showed that glutamic acid and aspartic acid are relatively inefficient in metal ion binding. From these studies, we suggest that Aβ-chelated Zn(II) is readily displaced by Cu(II) and Fe(III) ions and leads to a propagation of oxidative stress.
Keywords: Alzheimer's disease, amyloid-β peptide, aspartic acid, Fenton reaction, histidine, glutamic acid, metal ion chelation, NMR titrations, oxidative stress, tyrosine
