Editorial Board Chair PR Shepherd - Auckland Vice Chair, The Americas G Salvesen - La Jolla, CA Vice Chair, Asia-Pacific T Xu - Beijing Vice Chair, Europe DR Alessi - Dundee Vice Chair, Reviews A Toker - Boston, MA Deputy Chairs - BJ Cell D Hoekstra - Groningen M Schwartz - Charlottesville, VA Editors - BJ Cell RA Anderson - Madison, WI J Backer - Bronx, NY J Blank - Cambridge, MA LH Boise - Atlanta, GA P Booth - Bristol JF Caceres - Edinburgh L Chernomordik - Bethesda, MD AC Clark - Raleigh, NC R Docampo - Athens, GA C Duckett - Ann Arbor, MI AF Dulhunty - Canberra P Fay - Rochester, NY R Golsteyn - Lethbridge, AB DA Jans - Monash D Laird - London, Ont. K Lingelbach - Marburg L Machesky - Glasgow E Manser - Singapore J Miernyk - Columbia, MO H Naim - Hannover PF Pilch - Boston, MA A Postle - Southampton M Seabra - London FJ Sharom - Guelph, Ont. E Smythe - Sheffield S Stack - Columbia, MO H Stenmark - Oslo M Torti - Pavia HD Ulrich - South Mimms H Yagisawa - Hyogo-Ken C Zurzolo - Paris
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Biochem. J. (2007) 407
(435–450) (Printed in Great Britain)
Differential modulation of Alzheimer's disease amyloid b-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*†§ and 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, §Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria 3052, Australia, and Department of Biochemistry and Molecular Biology, The University of Melbourne, Victoria 3010, Australia
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 Ab (amyloid b) peptide. In the present study, we have further investigated the biochemical mechanisms by which metal ligands affect Ab metabolism. To achieve this, we measured the effects of diverse metal ligands on cellular metal uptake and secreted Ab 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 Ab. Generally, the ability to inhibit Ab 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 Ab levels while only inducing minimal change to cellular metal levels. Metal ligands that inhibited Ab 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 Ab. 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 Ab. 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.
Key words: Alzheimer's disease, amyloid, c-Jun N-terminal kinase (JNK), copper, metal complex, metalloprotease.
Abbreviations used: Ab, amyloid b; 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.
1To whom correspondence should be addressed (email arwhite@unimelb.edu.au).
Received 30 April 2007/3 August 2007; accepted 6 August 2007
Published as BJ Immediate Publication 6 August 2007, doi:10.1042/BJ20070579
© The Authors Journal compilation © 2007 Biochemical Society
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