Sequestration of copper from beta-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, Yan-mei Li

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94 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)31657–31664
Number of pages8
JournalThe Journal of Biological Chemistry
Volume283
Issue number46
DOIs
Publication statusPublished - 14 Nov 2008

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    Wu, W., Lei, P., Liu, Q., Hu, J., Gunn, A. P., Chen, M., Rui, Y., Su, X., Xie, Z., Zhao, Y-F., Bush, A. I., & Li, Y. (2008). Sequestration of copper from beta-amyloid promotes selective lysis by cyclen-hybrid cleavage agents. The Journal of Biological Chemistry, 283(46), 31657–31664. https://doi.org/10.1074/jbc.M804722200