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J. Biol. Chem., Vol. 283, Issue 8, 4568-4577, February 22, 2008

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Selective Intracellular Release of Copper and Zinc Ions from Bis(thiosemicarbazonato) Complexes Reduces Levels of Alzheimer Disease Amyloid-β Peptide^*

Paul S. Donnelly¹, Aphrodite Caragounis^¶||**, Tai Du^¶||**, Katrina M. Laughton^¶||, Irene Volitakis^¶||, Robert A. Cherny^¶||, Robyn A. Sharples^¶||, Andrew F. Hill^¶||, Qiao-Xin Li^¶||, Colin L. Masters^¶||**, Kevin J. Barnham^¶||, and Anthony R. White^¶||**2

From the School of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia, the Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia, the ^¶Department of Pathology, The University of Melbourne, Victoria 3010, Australia, the ^||Mental Health Research Institute, Parkville, Victoria 3052, Australia, the ^**Centre for Neuroscience, The University of Melbourne, Victoria 3010, Australia, and the Department of Biochemistry & Molecular Biology, The University of Melbourne, Parkville, Victoria 3010, Australia

Copper and zinc play important roles in Alzheimer disease pathology with recent reports describing potential therapeutics based on modulation of metal bioavailability. We examined the ability of a range of metal bis(thiosemicarbazonato) complexes (M^II(btsc), where M = Cu^II or Zn^II) to increase intracellular metal levels in Chinese hamster ovary cells overexpressing amyloid precursor protein (APP-CHO) and the subsequent effect on extracellular levels of amyloid-β peptide (Aβ). The Cu^II(btsc) complexes were engineered to be either stable to both a change in oxidation state and dissociation of metal or susceptible to intracellular reduction and dissociation of metal. Treatment of APP-CHO cells with stable complexes resulted in elevated levels of intracellular copper with no effect on the detected levels of Aβ. Treatment with complexes susceptible to intracellular reduction increased intracellular copper levels but also resulted in a dose-dependent reduction in the levels of monomeric Aβ. Treatment with less stable Zn^II(btsc) complexes increased intracellular zinc levels with a subsequent dose-dependent depletion of monomeric Aβ levels. The increased levels of intracellular bioavailable copper and zinc initiated a signaling cascade involving activation of phosphoinositol 3-kinase and c-Jun N-terminal kinase. Inhibition of these enzymes prevented Aβ depletion induced by the M^II(btsc) complexes. Inhibition of metalloproteases also partially restored Aβ levels, implicating metal-driven metalloprotease activation in the extracellular monomeric Aβ depletion. However, a role for alternative metal-induced Aβ metabolism has not been ruled out. These studies demonstrate that M^II(btsc) complexes have potential for Alzheimer disease therapy.

Received for publication, July 20, 2007 , and in revised form, December 11, 2007.

^* This work was supported by the National Health and Medical Research Council of Australia and the Australian Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental materials.

¹ To whom correspondence may be addressed: School of Chemistry, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. Tel.: 61-3-8344-2399; E-mail: pauld{at}unimelb.edu.au. ² To whom correspondence may be addressed: Dept. of Pathology and Centre for Neuroscience, The University of Melbourne, Victoria 3010, Australia. Tel.: 61-3-8344-1805; E-mail: arwhite{at}unimelb.edu.au.

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