Biometals have an important role in AD (Alzheimer's disease) and metal ligands have been investigated as potential therapeutic agents for treatment of AD. In recent studies the 8HQ (8-hydroxyquinoline) derivative CQ (clioquinol) has shown promising results in animal models and small clinical trials; however, the actual mode of action in vivo is still being investigated. We previously reported that CQ–metal complexes up-regulated MMP (matrix metalloprotease) activity in vitro by activating PI3K (phosphoinositide 3-kinase) and JNK (c-jun N-terminal kinase), and that the increased MMP activity resulted in enhanced degradation of secreted Aβ (amyloid β) peptide. In the present study, we have further investigated the biochemical mechanisms by which metal ligands affect Aβ metabolism. To achieve this, we measured the effects of diverse metal ligands on cellular metal uptake and secreted Aβ levels in cell culture. We report that different classes of metal ligands including 8HQ and phenanthroline derivatives and the sulfur compound PDTC (pyrrolidine dithiocarbamate) elevated cellular metal levels (copper and zinc), and resulted in substantial loss of secreted Aβ. Generally, the ability to inhibit Aβ levels correlated with a higher lipid solubility of the ligands and their capacity to increase metal uptake. However, we also identified several ligands that potently inhibited Aβ levels while only inducing minimal change to cellular metal levels. Metal ligands that inhibited Aβ levels [e.g. CQ, 8HQ, NC (neocuproine), 1,10-phenanthroline and PDTC] induced metal-dependent activation of PI3K and JNK, resulting in JNK-mediated up-regulation of metalloprotease activity and subsequent loss of secreted Aβ. The findings in the present study show that diverse metal ligands with high lipid solubility can elevate cellular metal levels resulting in metalloprotease-dependent inhibition of Aβ. Given that a structurally diverse array of ligands was assessed, the results are consistent with the effects being due to metal transport rather than the chelating ligand interacting directly with a receptor.
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November 2007
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Research Article|
October 12 2007
Differential modulation of Alzheimer's disease amyloid β-peptide accumulation by diverse classes of metal ligands
Aphrodite Caragounis;
Aphrodite Caragounis
*Department of Pathology, The University of Melbourne, Victoria 3010, Australia
†The Mental Health Research Institute, Parkville, Victoria 3052, Australia
‡Centre for Neuroscience, The University of Melbourne, Victoria 3010, Australia
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Tai Du;
Tai Du
*Department of Pathology, The University of Melbourne, Victoria 3010, Australia
†The Mental Health Research Institute, Parkville, Victoria 3052, Australia
‡Centre for Neuroscience, The University of Melbourne, Victoria 3010, Australia
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Gulay Filiz;
Gulay Filiz
*Department of Pathology, The University of Melbourne, Victoria 3010, Australia
†The Mental Health Research Institute, Parkville, Victoria 3052, Australia
‡Centre for Neuroscience, The University of Melbourne, Victoria 3010, Australia
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Katrina M. Laughton;
Katrina M. Laughton
*Department of Pathology, The University of Melbourne, Victoria 3010, Australia
†The Mental Health Research Institute, Parkville, Victoria 3052, Australia
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Irene Volitakis;
Irene Volitakis
*Department of Pathology, The University of Melbourne, Victoria 3010, Australia
‡Centre for Neuroscience, The University of Melbourne, Victoria 3010, Australia
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Robyn A. Sharples;
Robyn A. Sharples
*Department of Pathology, The University of Melbourne, Victoria 3010, Australia
†The Mental Health Research Institute, Parkville, Victoria 3052, Australia
§Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria 3052, Australia
∥Department of Biochemistry and Molecular Biology, The University of Melbourne, Victoria 3010, Australia
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Robert A. Cherny;
Robert A. Cherny
*Department of Pathology, The University of Melbourne, Victoria 3010, Australia
†The Mental Health Research Institute, Parkville, Victoria 3052, Australia
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Colin L. Masters;
Colin L. Masters
*Department of Pathology, The University of Melbourne, Victoria 3010, Australia
†The Mental Health Research Institute, Parkville, Victoria 3052, Australia
‡Centre for Neuroscience, The University of Melbourne, Victoria 3010, Australia
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Simon C. Drew;
Simon C. Drew
*Department of Pathology, The University of Melbourne, Victoria 3010, Australia
†The Mental Health Research Institute, Parkville, Victoria 3052, Australia
§Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria 3052, Australia
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Andrew F. Hill;
Andrew F. Hill
*Department of Pathology, The University of Melbourne, Victoria 3010, Australia
†The Mental Health Research Institute, Parkville, Victoria 3052, Australia
§Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria 3052, Australia
∥Department of Biochemistry and Molecular Biology, The University of Melbourne, Victoria 3010, Australia
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Qiao-Xin Li;
Qiao-Xin Li
*Department of Pathology, The University of Melbourne, Victoria 3010, Australia
†The Mental Health Research Institute, Parkville, Victoria 3052, Australia
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Peter J. Crouch;
Peter J. Crouch
*Department of Pathology, The University of Melbourne, Victoria 3010, Australia
†The Mental Health Research Institute, Parkville, Victoria 3052, Australia
‡Centre for Neuroscience, The University of Melbourne, Victoria 3010, Australia
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Kevin J. Barnham;
Kevin J. Barnham
*Department of Pathology, The University of Melbourne, Victoria 3010, Australia
†The Mental Health Research Institute, Parkville, Victoria 3052, Australia
§Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria 3052, Australia
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Anthony R. White
Anthony R. White
1
*Department of Pathology, The University of Melbourne, Victoria 3010, Australia
†The Mental Health Research Institute, Parkville, Victoria 3052, Australia
‡Centre for Neuroscience, The University of Melbourne, Victoria 3010, Australia
1To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
April 30 2007
Revision Received:
August 03 2007
Accepted:
August 06 2007
Accepted Manuscript online:
August 06 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2007 Biochemical Society
2007
Biochem J (2007) 407 (3): 435–450.
Article history
Received:
April 30 2007
Revision Received:
August 03 2007
Accepted:
August 06 2007
Accepted Manuscript online:
August 06 2007
Citation
Aphrodite Caragounis, Tai Du, Gulay Filiz, Katrina M. Laughton, Irene Volitakis, Robyn A. Sharples, Robert A. Cherny, Colin L. Masters, Simon C. Drew, Andrew F. Hill, Qiao-Xin Li, Peter J. Crouch, Kevin J. Barnham, Anthony R. White; Differential modulation of Alzheimer's disease amyloid β-peptide accumulation by diverse classes of metal ligands. Biochem J 1 November 2007; 407 (3): 435–450. doi: https://doi.org/10.1042/BJ20070579
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