Thermodynamic Investigation of Copper Binding to the Amyloid-Beta (A&beta) Peptide

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)
Cristina Sacco (Creator)
East Carolina University (ECU )
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Abstract: 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-β (Aβ) 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 Aβ 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 Aβ 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 Aβ peptide using isothermal titration calorimetry (ITC). Our goal is to understand the thermodynamics of copper binding to Aβ and give insight into the residues suspected in binding. We have studied copper binding to the shorter Aβ16 and Aβ28 along with Ac-Aβ16 and Ac-Aβ28 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 Aβ28(H6A), Aβ28(H13A), and Aβ28(H14A). These studies provide information about the metal binding site of Aβ. Understanding copper coordination and affinity to Aβ may give insight regarding metal chelators that can be used for drug therapy.  

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Date: 2010
Chemistry, Biochemistry, Chemistry, Inorganic

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