Sequestration of copper from beta-amyloid promotes selective lysis by cyclen-hybrid cleavage agents.
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.
Wu
Wei-hui
WH
Department of Chemistry, Tsinghua University, Beijing 100084, China.
Lei
Peng
P
Liu
Qian
Q
Hu
Jia
J
Gunn
Adam P
AP
Chen
Mei-sha
MS
Rui
Yan-fang
YF
Su
Xiao-yang
XY
Xie
Zuo-ping
ZP
Zhao
Yu-Fen
YF
Bush
Ashley I
AI
Li
Yan-mei
YM
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity / Q000648:ultrastructure; D000818:Animals; D002460:Cell Line; D003300:Copper / Q000378:metabolism*; D000080027:Cyclams; D006571:Heterocyclic Compounds / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009602:Nitrosamines; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D046509:Tissue Culture Techniques
D016229:Amyloid beta-Peptides; D000080027:Cyclams; D006571:Heterocyclic Compounds; D009602:Nitrosamines; D010455:Peptides; C036250:1-acetyl-1-methyl-2-nitroso-2-phenylhydrazine; D003300:Copper; C038072:cyclen; D006861:Hydrogen Peroxide