Alzheimer's disease is a fatal neurodegenerative disease that has claimed as many as 5.3 million Americans.  One of the characteristic hallmarks of Alzheimer's is the amyloid plaques that build up around the neurons.  The aggregated amyloid-� (A�) peptide is one of the main components of the amyloid plaques found in the brains of individuals with Alzheimer's disease.  Interestingly, high concentrations of metals (copper, zinc and iron) have been found inside these amyloid plaques.  The A� peptide can be either 40 or 42 residues in length but studies have shownthe metal binding site is within the first 16 residues.  Copper interactions with A� have been studied extensively via various spectroscopic methods and 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 thermodynamics of Cu2+ binding to truncated forms of the A� peptides using isothermal titration calorimetry (ITC) and ACES as buffer and weakly coordinating ligand have been obtained.  The data reveal that the overall free energy of Cu2+ binding to three A�28 mutants�where a potential histidine ligand was replaced by a non-coordinating alanine�is very similar to that of wild type A�28.  Furthermore, the data show that this is the result of entropy/enthalpy compensation where the removal of a histidine ligand resulted in an increase in entropy and a decrease in the enthalpy of Cu2+ binding.   To investigate this effect further, the heat capacity (?Cp) of Cu2+ binding to these peptides as well as the rat variant were obtained via ITC.  These data as well as potential mechanisms of oligomerization will be discussed.

Lessons learned from the enthalpy, entropy, and heat capacity of metal ions binding to biomolecules: A detailed study of copper(II) binding to A� peptides

248th National Meeting (2014)

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