Platinum-based Inhibitors of Amyloid-beta As Therapeutic Agents for Alzheimer's Disease

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2008 May 9

PMID 18463291

Citations 38

Authors

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

Roberto Cappai

Affiliations

Soon will be listed here.

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.

Citing Articles

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Replica exchange molecular dynamics simulation of the coordination of Pt(ii)-Phenanthroline to amyloid-β.

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References

BURDICK D, Soreghan B, Kwon M, Kosmoski J, Knauer M, Henschen A . Assembly and aggregation properties of synthetic Alzheimer's A4/beta amyloid peptide analogs. J Biol Chem. 1992; 267(1):546-54. View

Fanizzi F, Natile G, Lanfranchi M, Tiripicchio A, Laschi F, Zanello P . Steric Crowding and Redox Reactivity in Platinum(II) and Platinum(IV) Complexes Containing Substituted 1,10-Phenanthrolines. Inorg Chem. 1996; 35(11):3173-3182. DOI: 10.1021/ic960125y. View

Hardy J, Selkoe D . The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002; 297(5580):353-6. DOI: 10.1126/science.1072994. View

Lisman J . Long-term potentiation: outstanding questions and attempted synthesis. Philos Trans R Soc Lond B Biol Sci. 2003; 358(1432):829-42. PMC: 1693147. DOI: 10.1098/rstb.2002.1242. View

Opazo C, Huang X, Cherny R, Moir R, Roher A, White A . Metalloenzyme-like activity of Alzheimer's disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H(2)O(2). J Biol Chem. 2002; 277(43):40302-8. DOI: 10.1074/jbc.M206428200. View

Tickler A, Smith D, Ciccotosto G, Tew D, Curtain C, Carrington D . Methylation of the imidazole side chains of the Alzheimer disease amyloid-beta peptide results in abolition of superoxide dismutase-like structures and inhibition of neurotoxicity. J Biol Chem. 2005; 280(14):13355-63. DOI: 10.1074/jbc.M414178200. View

Varadarajan S, Kanski J, Aksenova M, Lauderback C, Butterfield D . Different mechanisms of oxidative stress and neurotoxicity for Alzheimer's A beta(1--42) and A beta(25--35). J Am Chem Soc. 2001; 123(24):5625-31. DOI: 10.1021/ja010452r. View

Hardy J . Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 1997; 20(4):154-9. DOI: 10.1016/s0166-2236(96)01030-2. View

Barnham K, Ciccotosto G, Tickler A, Ali F, Smith D, Williamson N . Neurotoxic, redox-competent Alzheimer's beta-amyloid is released from lipid membrane by methionine oxidation. J Biol Chem. 2003; 278(44):42959-65. DOI: 10.1074/jbc.M305494200. View

10.

Smith D, Smith D, Curtain C, Boas J, Pilbrow J, Ciccotosto G . Copper-mediated amyloid-beta toxicity is associated with an intermolecular histidine bridge. J Biol Chem. 2006; 281(22):15145-54. DOI: 10.1074/jbc.M600417200. View

11.

Takahara P, Rosenzweig A, Frederick C, Lippard S . Crystal structure of double-stranded DNA containing the major adduct of the anticancer drug cisplatin. Nature. 1995; 377(6550):649-52. DOI: 10.1038/377649a0. View

12.

Townsend M, Shankar G, Mehta T, Walsh D, Selkoe D . Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers. J Physiol. 2006; 572(Pt 2):477-92. PMC: 1779683. DOI: 10.1113/jphysiol.2005.103754. View

13.

Ciccotosto G, Tew D, Curtain C, Smith D, Carrington D, Masters C . Enhanced toxicity and cellular binding of a modified amyloid beta peptide with a methionine to valine substitution. J Biol Chem. 2004; 279(41):42528-34. DOI: 10.1074/jbc.M406465200. View

14.

Yao S, Cherny R, Bush A, Masters C, Barnham K . Characterizing bathocuproine self-association and subsequent binding to Alzheimer's disease amyloid beta-peptide by NMR. J Pept Sci. 2004; 10(4):210-7. DOI: 10.1002/psc.539. View

15.

Lee J, Stimson E, Ghilardi J, Mantyh P, Lu Y, Felix A . 1H NMR of A beta amyloid peptide congeners in water solution. Conformational changes correlate with plaque competence. Biochemistry. 1995; 34(15):5191-200. DOI: 10.1021/bi00015a033. View

16.

Atwood C, Scarpa R, Huang X, Moir R, Jones W, Fairlie D . Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1-42. J Neurochem. 2000; 75(3):1219-33. DOI: 10.1046/j.1471-4159.2000.0751219.x. View

17.

Simmons L, May P, Tomaselli K, Rydel R, Fuson K, Brigham E . Secondary structure of amyloid beta peptide correlates with neurotoxic activity in vitro. Mol Pharmacol. 1994; 45(3):373-9. View

18.

Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M . Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002; 416(6880):535-9. DOI: 10.1038/416535a. View

19.

Tsodyks M . Spike-timing-dependent synaptic plasticity - the long road towards understanding neuronal mechanisms of learning and memory. Trends Neurosci. 2002; 25(12):599-600. DOI: 10.1016/s0166-2236(02)02294-4. View

20.

Porat Y, Abramowitz A, Gazit E . Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chem Biol Drug Des. 2006; 67(1):27-37. DOI: 10.1111/j.1747-0285.2005.00318.x. View