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

Neurodegeneration observed in Alzheimer disease (AD) is believed to be related to the toxicity from reactive oxygen species (ROS) produced in the brain by the amyloid-beta (Ab) protein bound primarily to copper ions. The evidence for an oxidative stress role of A beta-Cu redox chemistry is still incomplete. Details of the copper binding site in Ab may be critical to the etiology of AD. Here we present the structure determined by combining x-ray absorption spectroscopy (XAS) and density functional theory analysis of Ab peptides complexed with Cu2+ in solution under a range of buffer conditions. Phosphate-buffered saline buffer salt (NaCl) concentration does not affect the high-affinity copper binding mode but alters the second coordination sphere. The XAS spectra for truncated and full-length A beta-Cu2+ peptides are similar. The novel distorted six-coordinated (3N3O) geometry around copper in the A beta-Cu2+ complexes include three histidines: glutamic, or/and aspartic acid, and axial water. The structure of the high-affinity Cu2+ binding site is consistent with the hypothesis that the redox activity of the metal ion bound to A beta can lead to the formation of dityrosine-linked dimers found in AD.