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 aggregated beta-amyloid peptide, whether in the form of plaques or soluble oligomers, is determined at least in part by high-affinity binding of transition metals, especially copper and zinc. Of the two metals, copper is implicated in reactive oxygen species generating reactions, while zinc appears to be associated with conformational and antioxidant activity. We tested the copper chelators trientine, penicillamine, and bathophenanthroline for their ability to mobilize brain A beta as measured against our benchmark compound bathocuproine (BC). All of these agents were effective in solubilizing brain A beta, although BC was the most consistent across the range of AD brain tissue samples tested. Similarly, all of the copper chelators depleted copper in the high-speed supernatants. BC alone had no significant effect upon zinc levels in the soluble fraction. BC extraction of brain tissue from C100 transgenic mice (which express human A beta but do not develop amyloid) revealed SDS-resistant dimers as A beta was mobilized from the sediment;able to the soluble fraction. NMR analysis showed that, in addition to its copper chelating properties, BC interacts with A beta to form a complex independent of the presence of copper. Such hybrid copper chelating and "chain breaking" properties may form the basis of a rational design for a therapy for Alzheimer's disease. (C) 2000 Academic Press.