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

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