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A major source of neurodegeneration observed in Alzheimer’s disease (AD) is believed to be related to the toxicity from reactive oxygen species (ROS) produced in the brain by the Amyloid-β (Aβ) protein bound primarily to copper ions. The evidence for an oxidative stress role of Aβ-Cu redox chemistry is still incomplete. Details of the copper binding site in Aβ may be critical to the etiology of AD. Here we present the structure determined by combining X-ray absorption fine structure (XAFS) and Density Functional Theory analysis of truncated Aβ(1-16) peptide complexed with Cu(II) in solution under a range of buffer conditions. PBS buffer salt (NaCl) concentration does not affect the copper binding mode. The XAFS spectra for truncated Aβ(1-16)-Cu(II) and full length Aβ(1-40/42)-Cu(II) peptides are similar. The novel six-coordinated (3N3O) geometry around copper in the Aβ-Cu(II) complex includes three histidines, glutamic or/and aspartic acid and axial water. The structure of high affinity Cu2+ binding site is consistent with the hypothesis that the redox activity of the metal ion bound to Aβ can lead to the formation of di-tyrosine linked dimers found in AD. X-ray absorption near-edge spectroscopy (XANES) has been used to probe the substrate mediated reduction of Cu(II) to Cu(I) in Aβ-Cu(II) complexes by ascorbate and the neurotoxin 6-hydroxydopamine (6-OHDA), however dopamine and, in particular, cholesterol are incapable of reducing soluble monomeric Aβ-Cu(II) complexes. The results are in agreement with assignment of the redox potentials for Aβ-Cu(II), ascorbic acid and dopamine.

The structure of the amyloid β-peptide high-affinity copper(II)-binding site in Alzheimer's disease