αB-crystallin competes with Alzheimer's disease β-amyloid peptide for peptide-peptide interactions and induces oxidation of Abeta-Met35

Alzheimer's disease (AD) is associated with plaque deposition in the brain of AD patients. The major component of the aggregate is a 39-12 long peptide termed beta-amyloid (A beta). Except for A beta, plaques contain several other components which co-precipitate together with AD. One such component is the small heat shock protein (sHSP) alpha B-crystallin. Instead of preventing the cell from the neurotoxicity of A beta, alpha B-crystallin induces an increased neurotoxicity. We find-using solution state NMR spectroscopy-that alpha B-crystallin competes efficiently for A beta monomer-monomer interactions. Interactions between A beta and aB-crystallin involve the hydrophobic core residues 17-21 as well as residues 31-32 of A beta, and thus the same chemical groups which are important for A beta aggregation. In the presence of aB-crystallin, Met35 in AD becomes efficiently oxidized. In order to quantify the redox properties of the different complexes consisting of A beta/alpha B-crystallin/copper, we suggest an NMR assay which allows to estimate the electrochemical properties indirectly by monitoring the rate of glutathion (GSH) auto-oxidation. The oxidation of the side chain Met35 in A beta might account for the increased neurotoxicity and the inability of A beta to form fibrillar structures, which has been observed previously in the presence of alpha B-crystallin [Stege, G.J. et al. (1999) The molecular chaperone alpha B-crystallin enhances amyloid-beta neurotoxicity. Biochem. Biophys. Res. Commun. 262, 152-156.]. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.