Zinc-induced Alzheimer's A beta 1-40 aggregation is mediated by conformational factors

The heterogeneous precipitates of A beta that accumulate in the brain cortex in Alzheimer's disease possess varying degrees of resistance to resolubilization. We previously found that A beta 1-40 is rapidly precipitated in vitro by physiological concentrations of zinc, a neurochemical that is highly abundant in brain compartments where A beta is most likely to precipitate. We now present evidence that the zinc-induced precipitation of A beta is mediated by a peptide dimer and favored by conditions that promote alpha-helical and diminish beta-sheet conformations. The manner in which the synthetic peptide is solubilized was critical to its behavior in vitro. Zinc-induced A beta aggregation was dependent upon the presence of NaCl, was enhanced when the peptide stock solution was stored frozen. The A beta aggregates induced by zinc were reversible by chelation, but could then be reprecipitated by zinc for several cycles, indicating that the peptide's conformation is probably preserved in the zinc-mediated assembly. In contrast, A beta aggregates induced by low pH (5.5) were not resolubilized by returning the pH milieu to 7.4. The zinc-A beta interaction exhibits features resembling the gelation process of zinc-mediated fibrin assembly, suggesting that, in events such as clot formation or injury, reversible A beta assembly could be physiologically purposive. Such a mechanism is contemplated in the early evolution of diffuse plaques in Alzheimer's disease and suggests a possible therapeutic strategy for the resolubilization of some forms of A beta deposit in the disease.