Thermodynamic investigation of copper binding to the amyloid-beta (Abeta) peptid

Alzheimer's disease is a fatal and neurodegenerative disease with as many as 5.3 million Americans living with the disease. One of the characteristic hallmarks of Alzheimer's is the amyloid plaques that build up around the neurons. The aggregated amyloid-beta (Abeta) peptide is one of the main components of the amyloid plaques found in individuals with Alzheimer's disease. Interestingly, high concentrations of metals (copper, zinc and iron) were found inside these amyloid plaques. The Abeta peptide can be either 40 or 42 residues in length but studies have shown the metal binding site is within the first 16 residues. Copper interactions with Abeta have been studied extensively, but there is no consensus on the coordinating ligands and binding affinity of metal to the peptide. The residues suspected in binding are the N-terminus (N-terminal amine or aspartate group), and the histidines in positions 6, 13, and 14.;The purpose of this research is to study the thermodynamics of copper binding to the Abeta peptide using isothermal titration calorimetry (ITC). Our goal is to understand the thermodynamics of copper binding to Abeta and give insight into the residues suspected in binding. We have studied copper binding to the shorter Abeta16 and Abeta28 along with Ac-Abeta16 and Ac-Abeta28 to determine the thermodynamic contribution from the N-terminus. We have observed a thermodynamic difference between the acetylated and nonacetylated forms of the peptide. We have also studied the thermodynamic contributions of the three histidine residues by studying copper binding to Abeta28(H6A), Abeta28(H13A), and Abeta28(H14A). These studies provide information about the metal binding site of Abeta. Understanding copper coordination and affinity to Abeta may give insight regarding metal chelators that can be used for drug therapy.