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J. Biol. Chem., Vol. 281, Issue 26, 17670-17680, June 30, 2006

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Degradation of the Alzheimer Disease Amyloid -Peptide by Metal-dependent Up-regulation of Metalloprotease Activity^*

Anthony R. White^¶1, Tai Du^¶, Katrina M. Laughton, Irene Volitakis, Robyn A. Sharples^||**, Michel E. Xilinas, David E. Hoke², R. M. Damian Holsinger, Geneviève Evin, Robert A. Cherny, Andrew F. Hill^||**, Kevin J. Barnham, Qiao-Xin Li, Ashley I. Bush³, and Colin L. Masters^¶

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

Biometals play an important role in Alzheimer disease, and recent reports have described the development of potential therapeutic agents based on modulation of metal bioavailability. The metal ligand clioquinol (CQ) has shown promising results in animal models and small phase clinical trials; however, the actual mode of action in vivo has not been determined. We now report a novel effect of CQ on amyloid -peptide (A) metabolism in cell culture. Treatment of Chinese hamster ovary cells overexpressing amyloid precursor protein with CQ and Cu²⁺ or Zn²⁺ resulted in an 85–90% reduction of secreted A-(1–40) and A-(1–42) compared with untreated controls. Analogous effects were seen in amyloid precursor protein-overexpressing neuroblastoma cells. The secreted A was rapidly degraded through up-regulation of matrix metalloprotease (MMP)-2 and MMP-3 after addition of CQ and Cu²⁺. MMP activity was increased through activation of phosphoinositol 3-kinase and JNK. CQ and Cu²⁺ also promoted phosphorylation of glycogen synthase kinase-3, and this potentiated activation of JNK and loss of A-(1–40). Our findings identify an alternative mechanism of action for CQ in the reduction of A deposition in the brains of CQ-treated animals and potentially in Alzheimer disease patients.

Received for publication, March 16, 2006 , and in revised form, April 28, 2006.

^* This work was supported in part by the National Health and Medical Research Council of Australia. 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.

² Supported by Ruth L. Kirschstein National Research Service Award Individual Fellowship AG05887 from NIA, National Institutes of Health.

³ Supported by NIA Grant R01-AG12686 from the National Institutes of Health, the Alzheimer's Association, the American Health Assistance Foundation, and the Australian Research Council.

¹ Supported by an R. D. Wright fellowship from the National Health and Medical Research Council of Australia. To whom correspondence should be addressed: Dept. of Pathology, University of Melbourne, Cnr. Grattan St. and Royal Parade, Victoria 3010, Australia. Tel.: 61-3-8344-1805; Fax: 61-3-9349-4004; E-mail: arwhite{at}unimelb.edu.au.

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