The Native Copper- and Zinc- Binding Protein Metallothionein Blocks Copper-Mediated Aβ Aggregation and Toxicity in Rat Cortical Neurons

Background: A major pathological hallmark of AD is the deposition of insoluble extracellular beta-amyloid (A beta) plaques. There are compelling data suggesting that A beta aggregation is catalysed by reaction with the metals zinc and copper. Methodology/Principal Findings: We now report that the major human-expressed metallothionein (MT) subtype, MT-2A, is capable of preventing the in vitro copper-mediated aggregation of A beta(1-40) and A beta(1-42). This action of MT-2A appears to involve a metal-swap between Zn(7)MT-2A and Cu(II)-A beta, since neither Cu(10)MT-2A or carboxymethylated MT-2A blocked Cu(II)-A beta aggregation. Furthermore, Zn7MT-2A blocked Cu(II)-A beta induced changes in ionic homeostasis and subsequent neurotoxicity of cultured cortical neurons. Conclusions/Significance: These results indicate that MTs of the type represented by MT-2A are capable of protecting against A beta aggregation and toxicity. Given the recent interest in metal-chelation therapies for AD that remove metal from A beta leaving a metal-free A beta that can readily bind metals again, we believe that MT-2A might represent a different therapeutic approach as the metal exchange between MT and A beta leaves the A beta in a Zn-bound, relatively inert form.