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The Native Copper- and Zinc- Binding Protein Metallothionein Blocks Copper-Mediated Aβ Aggregation and Toxicity in Rat Cortical Neurons

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posted on 2023-05-17, 03:17 authored by Chung, RS, Howells, C, Eaton, ED, Svetlana ShabalaSvetlana Shabala, Zovo, K, Palumaa, P, Sillard, R, Adele WoodhouseAdele Woodhouse, William BennettWilliam Bennett, Shannon HuskinsShannon Huskins, James VickersJames Vickers, Adrian WestAdrian West
Background: A major pathological hallmark of AD is the deposition of insoluble extracellular b-amyloid (Ab) plaques. There are compelling data suggesting that Ab 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 Ab1–40 and Ab1–42. This action of MT-2A appears to involve a metal-swap between Zn7MT-2A and Cu(II)-Ab, since neither Cu10MT-2A or carboxymethylated MT-2A blocked Cu(II)-Ab aggregation. Furthermore, Zn7MT-2A blocked Cu(II)-Ab 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 Ab aggregation and toxicity. Given the recent interest in metal-chelation therapies for AD that remove metal from Ab leaving a metal-free Ab that can readily bind metals again, we believe that MT-2A might represent a different therapeutic approach as the metal exchange between MT and Ab leaves the Ab in a Zn-bound, relatively inert form.


Publication title

P L o S One










Menzies Institute for Medical Research


Public Library of Science

Place of publication

United States

Rights statement

Copyright © 2010 Chung et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

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  • Open

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Clinical health not elsewhere classified

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