Anti-amyloid beta activity of metallothionein-III is different from its neuronal growth inhibitory activity: structure-activity studies

Recent studies have shown that metallothionein-III (MT-III), but not MT-I or -II, antagonizes both the neurotrophic and neurotoxic effects of amyloid β peptides (Aβs). Further, its anti-Aβ-toxicity effect was attributed to the fact that it inhibits the formation of fibrillar Aβ. MT-III alone also affects neuron survival in culture—promoting at low but inhibiting at high concentrations. To characterize these biological activities of MT-III in relation to its neuronal growth inhibitory activity discovered by Uchida et al. [Neuron 7 (1991) 337–347], we here studied effects of the P7S/P9A double mutant, and the N- and C-terminal domains of MT-III on primary cultures of rat embryonic cortical neurons in the presence and absence of Aβ. Results show that (i) only the wild-type MT-III inhibited the formation of SDS-resistant Aβ aggregates and protected cortical neurons from the toxic effect of Aβ, and (ii) both the wild type and the N-terminal domain of MT-III promote neuron survival at low concentrations but inhibited it at high concentrations. On the basis of these findings, we conclude that the anti-Aβ activity of MT-III is different from its neuronal growth inhibitory activity and suggest that the increased trophic activity of AD brain extracts could be attributed to its low MT-III content.