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Research article

Differential modulation of Alzheimer's disease amyloid β-peptide accumulation by diverse classes of metal ligands

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
Biochemical Journal Nov 01, 2007, 407 (3) 435-450; DOI: 10.1042/BJ20070579
Aphrodite Caragounis
Department of Pathology, The University of Melbourne, Victoria 3010, AustraliaThe Mental Health Research Institute, Parkville, Victoria 3052, AustraliaCentre for Neuroscience, The University of Melbourne, Victoria 3010, Australia
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Tai Du
Department of Pathology, The University of Melbourne, Victoria 3010, AustraliaThe Mental Health Research Institute, Parkville, Victoria 3052, AustraliaCentre for Neuroscience, The University of Melbourne, Victoria 3010, Australia
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Gulay Filiz
Department of Pathology, The University of Melbourne, Victoria 3010, AustraliaThe Mental Health Research Institute, Parkville, Victoria 3052, AustraliaCentre for Neuroscience, The University of Melbourne, Victoria 3010, Australia
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Katrina M. Laughton
Department of Pathology, The University of Melbourne, Victoria 3010, AustraliaThe Mental Health Research Institute, Parkville, Victoria 3052, Australia
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Irene Volitakis
Department of Pathology, The University of Melbourne, Victoria 3010, AustraliaCentre for Neuroscience, The University of Melbourne, Victoria 3010, Australia
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Robyn A. Sharples
Department of Pathology, The University of Melbourne, Victoria 3010, AustraliaThe Mental Health Research Institute, Parkville, Victoria 3052, AustraliaBio21 Molecular Science and Biotechnology Institute, Parkville, Victoria 3052, AustraliaDepartment of Biochemistry and Molecular Biology, The University of Melbourne, Victoria 3010, Australia
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Robert A. Cherny
Department of Pathology, The University of Melbourne, Victoria 3010, AustraliaThe Mental Health Research Institute, Parkville, Victoria 3052, Australia
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Colin L. Masters
Department of Pathology, The University of Melbourne, Victoria 3010, AustraliaThe Mental Health Research Institute, Parkville, Victoria 3052, AustraliaCentre for Neuroscience, The University of Melbourne, Victoria 3010, Australia
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Simon C. Drew
Department of Pathology, The University of Melbourne, Victoria 3010, AustraliaThe Mental Health Research Institute, Parkville, Victoria 3052, AustraliaBio21 Molecular Science and Biotechnology Institute, Parkville, Victoria 3052, Australia
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Andrew F. Hill
Department of Pathology, The University of Melbourne, Victoria 3010, AustraliaThe Mental Health Research Institute, Parkville, Victoria 3052, AustraliaBio21 Molecular Science and Biotechnology Institute, Parkville, Victoria 3052, AustraliaDepartment of Biochemistry and Molecular Biology, The University of Melbourne, Victoria 3010, Australia
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Qiao-Xin Li
Department of Pathology, The University of Melbourne, Victoria 3010, AustraliaThe Mental Health Research Institute, Parkville, Victoria 3052, Australia
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Peter J. Crouch
Department of Pathology, The University of Melbourne, Victoria 3010, AustraliaThe Mental Health Research Institute, Parkville, Victoria 3052, AustraliaCentre for Neuroscience, The University of Melbourne, Victoria 3010, Australia
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Kevin J. Barnham
Department of Pathology, The University of Melbourne, Victoria 3010, AustraliaThe Mental Health Research Institute, Parkville, Victoria 3052, AustraliaBio21 Molecular Science and Biotechnology Institute, Parkville, Victoria 3052, Australia
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Anthony R. White
Department of Pathology, The University of Melbourne, Victoria 3010, AustraliaThe Mental Health Research Institute, Parkville, Victoria 3052, AustraliaCentre for Neuroscience, The University of Melbourne, Victoria 3010, Australia
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  • For correspondence: arwhite@unimelb.edu.au
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Abstract

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.

  • Alzheimer's disease
  • amyloid
  • c-Jun N-terminal kinase (JNK)
  • copper
  • metal complex
  • metalloprotease

Abbreviations: Aβ, amyloid β; AD, Alzheimer's disease; APP, amyloid precursor protein; BC, bathocuprione; BCS, bathocuproine sulfonate; BP, bathophenanthroline; BPS, bathophenanthroline disulfonate; CHO, Chinese-hamster ovary; CQ, clioquinol; DCF, 2′,7′-dichlorofluorescein; DCF-DA, DCF-diacetate; DFO, deferoximine; HRP, horseradish peroxidase; 8HQ, 8-hydroxyquinoline; ICP-MS, inductively coupled plasma MS; IRE, iron-responsive element; JNK, c-Jun N-terminal kinase; mAb, monoclonal antibody; MAPK, mitogen-activated protein kinase; MMP, matrix metalloprotease; MT, membrane-type; NC, neocuproine; PBST, PBS containing 0.05% (v/v) Tween 20; PDTC, pyrrolidine dithiocarbamate; PI3K, phosphoinositide 3-kinase; RFU, relative fluorescence unit; TM, tetrathiomolybdate

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November 2007

Volume: 407 Issue: 3

Biochemical Journal: 407 (3)
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Differential modulation of Alzheimer's disease amyloid β-peptide accumulation by diverse classes of metal ligands
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
Biochemical Journal Nov 2007, 407 (3) 435-450; DOI: 10.1042/BJ20070579
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Differential modulation of Alzheimer's disease amyloid β-peptide accumulation by diverse classes of metal ligands
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
Biochemical Journal Nov 2007, 407 (3) 435-450; DOI: 10.1042/BJ20070579

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Keywords

Alzheimer's disease
amyloid
c-Jun N-terminal kinase (JNK)
copper
metal complex
metalloprotease

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