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

Barnham, Kevin J., Kenche, Vijaya B., Ciccotosto, Giuseppe D., Smith, David P., Tew, Deborah J., Liu, Xiang, Perez, Keyla, Cranston, Greg A., Johanssen, Timothy J., Volitakis, Irene, Bush, Ashley I., Masters, Colin L., White, Anthony R., Smith, Jeffrey P., Cherny, Robert A., Cappai, Roberto
Proceedings of the National Academy of Sciences of the United States of America 2008 v.105 no.19 pp. 6813-6818
Alzheimer disease, amyloid, binding sites, cisplatin, ligands, mice, neurotoxicity, physicochemical properties, platinum, reactive oxygen species
Amelyoid-β peptide (Aβ) is a major causative agent responsible for Alzheimer's disease (AD). Aβ 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-PtCl₂ (L = 1,10-phenanthroline derivatives) complexes were examined and shown to bind to Aβ, inhibit neurotoxicity and rescue Aβ-induced synaptotoxicity in mouse hippocampal slices. Coordination of the complexes to Aβ 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 Aβ. This implies that the planar aromatic 1,10-phenanthroline ligands L confer some specificity for Aβ onto the platinum complexes. The potent effect of the L-PtCl₂ complexes identifies this class of compounds as therapeutic agents for AD.