Chelation and intercalation: Complementary properties in a compound for the treatment of Alzheimer's disease

Selective application of metal chelators to homogenates of human Alzheimer' s disease (AD) brain has led us to propose that the architecture of aggrega ted beta-amyloid peptide, whether in the form of plaques or soluble oligome rs, is determined at least in part by high-affinity binding of transition m etals, especially copper and zinc. Of the two metals, copper is implicated in reactive oxygen species generating reactions, while zinc appears to be a ssociated with conformational and antioxidant activity. We tested the coppe r chelators trientine, penicillamine, and bathophenanthroline for their abi lity to mobilize brain A beta as measured against our benchmark compound ba thocuproine (BC). All of these agents were effective in solubilizing brain A beta, although BC was the most consistent across the range of AD brain ti ssue samples tested. Similarly, all of the copper chelators depleted copper in the high-speed supernatants. BC alone had no significant effect upon zi nc levels in the soluble fraction. BC extraction of brain tissue from C100 transgenic mice (which express human A beta but do not develop amyloid) rev ealed SDS-resistant dimers as A beta was mobilized from the sediment;able t o the soluble fraction. NMR analysis showed that, in addition to its copper chelating properties, BC interacts with A beta to form a complex independe nt of the presence of copper. Such hybrid copper chelating and "chain break ing" properties may form the basis of a rational design for a therapy for A lzheimer's disease. (C) 2000 Academic Press.