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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.

Original publication

DOI

10.1073/pnas.0800712105

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

13/05/2008

Volume

105

Pages

6813 - 6818

Keywords

Alzheimer Disease, Amino Acid Sequence, Amyloid beta-Peptides, Animals, Circular Dichroism, Hydrogen Peroxide, Inhibitory Concentration 50, Long-Term Potentiation, Magnetic Resonance Spectroscopy, Mass Spectrometry, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Neurotoxins, Oxidation-Reduction, Platinum, Protein Structure, Quaternary, Protein Structure, Secondary, Synchrotrons