Metallothionein-III (MT-III) protects cerebral cortical neurons in established culture from the toxic effect of amyloid beta peptides (A betas), Protection is concentration dependent and approaches 100% at 0.1 muM. The EC50 value estimated at 5 muM A beta (1-40) is 2 nM. At higher concentrations (>0.1 muM), MT-III also antagonizes the trophic effect of A beta (1-40) on cerebral cortical neurons in early cultures. Because only the fibrillar, SDS-resistant form of A beta aggregates are thought to be neurotoxic, we analyzed and compared A beta (1-40) aggregates formed in the presence and absence of MT-III using SDS-PAGE. Results show that aggregates formed in the absence of MT-III are predominantly SDS-resistant whereas those formed in its presence are mostly SDS-soluble, Neither MT-I nor -II exhibits any of the effects of MT-III, On the basis of these results, we propose that MT-III alleviates A betas' neurotoxic effect by abolishing the formation of toxic aggregates of A betas and that it may play a specific and important role in protecting the brain from the deleterious effects of A betas.