Copper 2+ binding to Aβ accelerates fiber growth and enhances neurotoxicity

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• John H Viles, Queen Mary, University of London
• Thursday 20 October 2011, 14:00-15:00
• Bateson Room, Department of Genetics.

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Although Cu2+ ions are found concentrated within senile plaques of Alzheimer’s disease patients directly bound to A and in vivo studies have shown that impaired copper homeostasis enhances the toxic effects of A. A role for Cu2+ ions in Alzheimer’s disease (AD) is often disputed, as it is believed that Cu2+ ions have a relatively low affinity for A and promote non-toxic amorphous aggregates of amyloid- (A. In contrast with currently held opinion, we show that Cu2+ ions in fact doubles the rate of production of amyloid fibres, accelerating both the nucleation and elongation of fibre formation. We further show that Cu2+ ions bound to A are consistently more toxic to neuronal cells than A in the absence of Cu2+ ions. The affinity of Cu2+ for A is highly disputed. Our competition studies indicate a dissociation constant of 10-11 M, at pH 7.4, for both fibrillar and monomeric forms. Electron paramagnetic resonance studies (EPR) suggest a dynamic view of the tetragonal Cu2+ complex creating an ensemble of coordination geometries in exchange between each other. An active role for Cu2+ ions in accelerating fibre formation and promoting cell death coupled with the high affinity of Cu2+ for A, suggests impaired copper homeostasis could be a risk factor in Alzheimer’s disease.

[1] Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-β from Alzheimer Disease. Claire J. Sarell, Shane R. Wilkinson and John H. Viles (2010) J Biol Chem 285, 41533-41540.

[2] Cu(II) binding to amyloid-beta fibrils of Alzheimer’s Disease reveals a pico-molar affinity. CJ Sarell, CD Syme, SEJ Rigby and Viles JH (2009) Biochemistry 48, 4388-402

[3] Copper binding to the amyloid-beta (Aβ) peptide associated with Alzheimer’s disease. CD Syme, RC Nadal, SEJ Rigby and Viles JH (2004) J Biol Chem. 279, 18169-18177

This talk is part of the Genetics Seminar Series series.

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