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 beta peptides (Abetas). Further, its anti-Abeta-toxicity effect was attributed to the fact that it inhibits the formation of fibrillar Abeta. 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 Abeta. Results show that (i). only the wild-type MT-III inhibited the formation of SDS-resistant Abeta aggregates and protected cortical neurons from the toxic effect of Abeta, 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-Abeta 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.
Irie
Yoshifumi
Y
Department of Psychiatry at Massachusetts Mental Health Center, Harvard Medical School, One Kendall Square, Building 600, 3/F, Cambridge, MA 02139, USA.
Keung
Wing Ming
WM
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000633:toxicity; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007202:Indicators and Reagents; D000090023:Metallothionein 3; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D051381:Rats; D012967:Sodium Dodecyl Sulfate / Q000633:toxicity; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D007202:Indicators and Reagents; D000090023:Metallothionein 3; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D012967:Sodium Dodecyl Sulfate