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J. Biol. Chem., Vol. 281, Issue 22, 15145-15154, June 2, 2006

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Copper-mediated Amyloid- Toxicity Is Associated with an Intermolecular Histidine Bridge^*

David P. Smith¹, Danielle G. Smith, Cyril C. Curtain^¶, John F. Boas^¶, John R. Pilbrow^¶, Giuseppe D. Ciccotosto, Tong-Lay Lau^||, Deborah J. Tew, Keyla Perez, John D. Wade^**, Ashley I. Bush², Simon C. Drew, Frances Separovic^||, Colin L. Masters², Roberto Cappai^¶¶2, and Kevin J. Barnham²³

From the Department of Pathology, ^¶¶Centre for Neuroscience, and ^||School of Chemistry, University of Melbourne, Victoria 3010, Australia, the Mental Health Research Institute of Victoria, Victoria 3010, Australia, the ^¶School of Physics, Monash University, Victoria 3800, Australia, the ^**Howard Florey Institute of Medical Research, Victoria 3010, Australia, the Laboratory for Oxidation Biology, Genetics, and Aging Research Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, and the Centre for Magnetic Resonance and Centre for Metals in Biology, University of Queensland, Queensland 4072, Australia

Amyloid- peptide (A) is pivotal to the pathogenesis of Alzheimer disease. Here we report the formation of a toxic A-Cu²⁺ complex formed via a histidine-bridged dimer, as observed at Cu²⁺/peptide ratios of >0.6:1 by EPR spectroscopy. The toxicity of the A-Cu²⁺ complex to cultured primary cortical neurons was attenuated when either the -or -nitrogen of the imidazole side chains of His were methylated, thereby inhibiting formation of the His bridge. Toxicity did not correlate with the ability to form amyloid or perturb the acyl-chain region of a lipid membrane as measured by diphenyl-1,3,5-hexatriene anisotropy, but did correlate with lipid peroxidation and dityrosine formation. ³¹P magic angle spinning solid-state NMR showed that A and A-Cu²⁺ complexes interacted at the surface of a lipid membrane. These findings indicate that the generation of the A toxic species is modulated by the Cu²⁺ concentration and the ability to form an intermolecular His bridge.

Received for publication, January 17, 2006 , and in revised form, March 24, 2006.

^* This work was supported in part by the Wellcome Trust, National Health and Medical Research Council of Australia, Australian Research Council, and Prana Biotechnology Ltd. 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 Table 1 and Figs. 1–3.

¹ A Wellcome Travelling Fellow.

² Consultant to Prana Biotechnology Ltd.

³ To whom correspondence should be addressed: Dept. of Pathology, University of Melbourne, Victoria 3010, Australia. Tel.: 61-3-8344-1805; Fax: 61-3-8344-4004; E-mail: kbarnham{at}unimelb.edu.au.

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