Platinum-based inhibitors of amyloid-β as therapeutic agents for Alzheimer's disease
- Kevin J. Barnham*,†,‡,§,
- Vijaya B. Kenche*,†,‡,
- Giuseppe D. Ciccotosto*,†,‡,
- David P. Smith*,¶,
- Deborah J. Tew*,†,‡,
- Xiang Liu*,†,
- Keyla Perez*,†,‡,
- Greg A. Cranston*,†,‡,
- Timothy J. Johanssen*,†,‡,
- Irene Volitakis*,†,
- Ashley I. Bush*,†,
- Colin L. Masters*,†,‖,
- Anthony R. White*,†,‖,
- Jeffrey P. Smith*,†,
- Robert A. Cherny*,†, and
- Roberto Cappai*,†,‡
- *Department of Pathology,
- †The Mental Health Research Institute,
- ‡Bio21 Institute of Molecular Science and Biotechnology, and
- ‖Centre for Neuroscience, University of Melbourne, Parkville, Victoria, 3010, Australia
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Edited by Peter J. Sadler, University of Warwick, Coventry, United Kingdom, and accepted by the Editorial Board March 2, 2008 (received for review January 23, 2008)
Abstract
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.
Footnotes
- §To whom correspondence should be addressed. E-mail: kbarnham{at}unimelb.edu.au
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Author contributions: K.J.B. designed research; K.J.B., V.B.K., G.D.C., D.P.S., D.J.T., X.L., K.P., G.A.C., T.J.J., I.V., A.R.W., and J.P.S. performed research; A.I.B., C.L.M., R.A.C., and R.C. contributed new reagents/analytic tools; K.J.B., R.A.C., and R.C. analyzed data; and K.J.B. wrote the paper.
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↵ ¶Present address: Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
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Conflict of interest statement: K.J.B., A.I.B., C.L.M., R.A.C., and R.C. are consultants to Prana Biotechnology.
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This article is a PNAS Direct Submission. P.J.S. is a guest editor invited by the Editorial Board.
- © 2008 by The National Academy of Sciences of the USA
