The native copper- and zinc- binding protein metallothionein blocks copper-mediated aβ aggregation and toxicity in rat cortical neurons

Roger S. Chung, Claire Howells, Emma D. Eaton, Lana Shabala, Kairit Zovo, Peep Palumaa, Rannar Sillard, Adele Woodhouse, William R. Bennett, Shannon Ray, James C. Vickers, Adrian K. West

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)
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Abstract

Background: A major pathological hallmark of AD is the deposition of insoluble extracellular β-amyloid (Aβ) plaques. There are compelling data suggesting that Aβ aggregation is catalysed by reaction with the metals zinc and copper. Methodology/Principal Findings: We now report that the major human-expressed metallothionein (MT) subtype, MT-2A, is capable of preventing the in vitro copper-mediated aggregation of Aβ1-40 and Aβ1-42. This action of MT-2A appears to involve a metal-swap between Zn7MT-2A and Cu(II)-Aβ, since neither Cu10MT-2A or carboxymethylated MT-2A blocked Cu(II)-Aβ aggregation. Furthermore, Zn7MT-2A blocked Cu(II)-Aβ induced changes in ionic homeostasis and subsequent neurotoxicity of cultured cortical neurons. Conclusions/Significance: These results indicate that MTs of the type represented by MT-2A are capable of protecting against Aβ aggregation and toxicity. Given the recent interest in metal-chelation therapies for AD that remove metal from Aβ leaving a metal-free Aβ that can readily bind metals again, we believe that MT-2A might represent a different therapeutic approach as the metal exchange between MT and Aβ leaves the Aβ in a Zn-bound, relatively inert form.

Original languageEnglish
Article numbere12030
Pages (from-to)1-11
Number of pages11
JournalPLoS ONE
Volume5
Issue number8
DOIs
Publication statusPublished - Aug 2010
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2010. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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