ZINC-INDUCED ALZHEIMERS 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 pre cipitated in vitro by physiological concentrations of zinc, a neuroche mical that is highly abundant in brain compartments where A beta is mo st likely to precipitate. We now present evidence that the zinc-induce d precipitation of A beta is mediated by a peptide dimer and favored b y conditions that promote alpha-helical and diminish beta-sheet confor mations. 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 st ock 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 pro bably preserved in the zinc-mediated assembly. In contrast, A beta agg regates induced by low pH (5.5) were not resolubilized by returning th e pH milieu to 7.4. The zinc-A beta interaction exhibits features rese mbling the gelation process of zinc-mediated fibrin assembly, suggesti ng that, in events such as clot formation or injury, reversible A beta assembly could be physiologically purposive. Such a mechanism is cont emplated in the early evolution of diffuse plaques in Alzheimer's dise ase and suggests a possible therapeutic strategy for the resolubilizat ion of some forms of A beta deposit in the disease.