Cu2+ Binding to Aβ peptides: Detailed Heat Capacity Studies Provide Structural Insight into Complex Formation

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Sunitha Gade (Creator)

Institution

East Carolina University (ECU )

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

Advisor

Anne Spuches

Abstract: Alzheimer's disease (AD) an irreversible progressive and devastating neurodegenerative disease is the most common cause of dementia. It is characterized by the extracellular amyloid plaques and the intracellular neurofibrillary tangles. Amyloid plaques are majorly constituted of Aβ peptides which are cleaved from the membrane bound amyloid precursor protein (APP). Aβ peptides consist of either 40 or 42 amino acid residues. Elevated concentrations of copper zinc and iron have been measured in amyloid plaques and recent in vitro studies have shown that zinc and copper ions promote the aggregation of these peptides. Furthermore it was found that high affinity metal ion chelators can be used in the dissolution of aggregated Aβ peptides. Taken together these studies show the important role metal ions play in AD.  In vitro studies have shown that aggregation of human Aβ peptides increases due to the presence of Cu but this effect is much less profound for rat Aβ peptides. Previous studies indicate that Cu2+ binding occurs within the first 16 amino acid residues of the full length Aβ peptides. Our lab has investigated the thermodynamics of Cu2+ binding to Aβ16 Aβ28 and three variant peptides using isothermal titration calorimetry (ITC) and ACES buffer as a weak competing ligand. In this study the binding of Cu2+ to Aβ16 was studied at three different concentrations of ACES buffer (20mM 50mM and 100mM). Buffer independent binding constants (K) are then extracted to test for ternary complex formation. According to the thermodynamic studies of Cu2+ binding to Aβ28 and Aβ28 mutants a model was proposed which was further tested by obtaining the heat capacity (∆Cp) data for Cu2+ binding to Aβ16 Aβ28 and Aβ28 mutants. In addition heat capacity (∆Cp) data for Cu2+ binding to Rat Aβ28 is obtained and compared to human Aβ28. Taken together this data will be used to shed light on why the rat peptides do not form fibrils. 

Additional Information

Publication

Thesis

Date: 2012

Keywords

Chemistry, Inorganic chemistry,

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