Journal of Biological Chemistry
Volume 283, Issue 46, 14 November 2008, Pages 31657-31664
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Protein Synthesis, Post-Translational Modification, and Degradation
Sequestration of Copper from β-Amyloid Promotes Selective Lysis by Cyclen-Hybrid Cleavage Agents*

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Decelerated degradation of β-amyloid (Aβ) and its interaction with synaptic copper may be pathogenic in Alzheimer disease. Recently, Co(III)-cyclen tagged to an aromatic recognition motif was shown to degrade Aβ in vitro. Here, we report that apocyclen attached to selective Aβ recognition motifs (KLVFF or curcumin) can capture copper bound to Aβ and use the Cu(II) in place of Co(III) to become proteolytically active. The resultant complexes interfere with Aβ aggregation, degrade Aβ into fragments, preventing H2O2 formation and toxicity in neuronal cell culture. Because Aβ binds Cu in amyloid plaques, apocyclen-tagged targeting molecules may be a promising approach to the selective degradation of Aβ in Alzheimer disease. The principle of copper capture could generalize to other amyloidoses where copper is implicated.

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*

This work was supported by National Natural Science Foundation of China Grants 20825206 and 20672067 and by an Australian Research Council Federation fellowship and the National Health and Medical Research Council (to A. I. B.). 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 “Experimental Procedures,” Table S1, and Fig. S1.

1

Both authors contributed equally to this work.

2

Present address: Mental Health Research Institute of Victoria and Dept. of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia.