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The Journal of Biological Chemistry

Year: 2008  |  Volume: 283  |  Issue: 46  |  Page No.: 31657 - 31664

Sequestration of Copper from β-Amyloid Promotes Selective Lysis by Cyclen-Hybrid Cleavage Agents

Wei-hui Wu, Peng Lei, Qian Liu, Jia Hu, Adam P. Gunn, Mei-sha Chen, Yan-fang Rui, Xiao-yang Su, Zuo-ping Xie, Yu-Fen Zhao, Ashley I. Bush and Yan-mei Li

Abstract

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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