X-ray Absorption Spectroscopy Investigations of Copper(II) Coordination in the Human Amyloid ß Peptide.

ABSTRACT

Alzheimer's disease (AD) is the main cause of age-related dementia and currently affects approximately 5.7 million Americans. Major brain changes associated with AD pathology include accumulation of amyloid beta (Aß) protein fragments and formation of extracellular amyloid plaques. Redox-active metals mediate oligomerization of Aß, and the resultant metal-bound oligomers have been implicated in the putative formation of harmful, reactive species that could contribute to observed oxidative damage. In isolated plaque cores, Cu(II) is bound to Aß via histidine residues. Despite numerous structural studies of Cu(II) binding to synthetic Aß in vitro, there is still uncertainty surrounding Cu(II) coordination in Aß. In this study, we used X-ray absorption spectroscopy (XAS) and high energy resolution fluorescence detected (HERFD) XAS to investigate Cu(II) coordination in Aß(1-42) under various solution conditions. We found that the average coordination environment in Cu(II)Aß(1-42) is sensitive to X-ray photoreduction, changes in buffer composition, peptide concentration, and solution pH. Fitting of the extended X-ray absorption fine structure (EXAFS) suggests Cu(II) is bound in a mixture of coordination environments in monomeric Aß(1-42) under all conditions studied. However, it was evident that on average only a single histidine residue coordinates Cu(II) in monomeric Aß(1-42) at pH 6.1, in addition to 3 other oxygen or nitrogen ligands. Cu(II) coordination in Aß(1-42) at pH 7.4 is similarly 4-coordinate with oxygen and nitrogen ligands, although an average of 2 histidine residues appear to coordinate at this pH. At pH 9.0, the average Cu(II) coordination environment in Aß(1-42) appears to be 5-coordinate with oxygen and nitrogen ligands, including two histidine residues.