Platinum-based inhibitors of amyloid-beta as therapeutic agents for Alzheimer's disease

BARNHAM, K. J., KENCHE, V. B., CICCOTOSTO, G. D., SMITH, D. P., TEW, D. J., LIU, X., PEREZ, K., CRANSTON, G. A., JOHANSSEN, T. J., VOLITAKIS, I., BUSH, A. I., MASTERS, C. L., WHITE, A. R., SMITH, J. P., CHERNY, R. A. and CAPPAI, R. (2008). Platinum-based inhibitors of amyloid-beta as therapeutic agents for Alzheimer's disease. Proceedings of the National Academy of Sciences, 105 (19), 6813-6818.

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Official URL: http://dx.doi.org/10.1073/pnas.0800712105
Link to published version:: 10.1073/pnas.0800712105

Abstract

Amelyoid-beta peptide (Abeta) is a major causative agent responsible for Alzheimer's disease (AD). Abeta contains a high affinity metal binding site that modulates peptide aggregation and toxicity. Therefore, identifying molecules targeting this site represents a valid therapeutic strategy. To test this hypothesis, a range of L-PtCl(2) (L = 1,10-phenanthroline derivatives) complexes were examined and shown to bind to Abeta, inhibit neurotoxicity and rescue Abeta-induced synaptotoxicity in mouse hippocampal slices. Coordination of the complexes to Abeta altered the chemical properties of the peptide inhibiting amyloid formation and the generation of reactive oxygen species. In comparison, the classic anticancer drug cisplatin did not affect any of the biochemical and cellular effects of Abeta. This implies that the planar aromatic 1,10-phenanthroline ligands L confer some specificity for Abeta onto the platinum complexes. The potent effect of the L-PtCl(2) complexes identifies this class of compounds as therapeutic agents for AD.

Item Type: Article
Research Institute, Centre or Group: Biomedical Research Centre
Identification Number: 10.1073/pnas.0800712105
Depositing User: Rebecca Jones
Date Deposited: 01 Mar 2012 09:53
Last Modified: 01 Mar 2012 09:53
URI: http://shura.shu.ac.uk/id/eprint/4879

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