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)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Advisor

Anne M. Spuches

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-[beta] (A[beta]) 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 A[beta] 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 A[beta] 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 A[beta] peptide using isothermal titration calorimetry (ITC). Our goal is to understand the thermodynamics of copper binding to A[beta] and give insight into the residues suspected in binding. We have studied copper binding to the shorter A[beta]16 and A[beta]28 along with Ac-A[beta]16 and Ac-A[beta]28 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 A[beta]28(H6A) A[beta]28(H13A) and A[beta]28(H14A). These studies provide information about the metal binding site of A[beta]. Understanding copper coordination and affinity to A[beta] may give insight regarding metal chelators that can be used for drug therapy. 

Additional Information

Publication

Thesis

Date: 2012

Keywords

Chemistry, Inorganic, Chemistry, Biochemistry

Subjects

Alzheimer's disease

Copper

Amyloid beta-protein

Peptides

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