Journal
PLOS ONE
Volume 5, Issue 8, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0012030
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Funding
- Australian Research Council (ARC) [DP0556630, DP0984673, LP0774820]
- National Health and Medical Research Council [490025, 544913]
- Jack & Ethel Goldin Foundation
- Australian Research Council [DP0984673, LP0774820, DP0556630] Funding Source: Australian Research Council
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Background: A major pathological hallmark of AD is the deposition of insoluble extracellular beta-amyloid (A beta) plaques. There are compelling data suggesting that A beta 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 A beta(1-40) and A beta(1-42). This action of MT-2A appears to involve a metal-swap between Zn(7)MT-2A and Cu(II)-A beta, since neither Cu(10)MT-2A or carboxymethylated MT-2A blocked Cu(II)-A beta aggregation. Furthermore, Zn7MT-2A blocked Cu(II)-A beta 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 A beta aggregation and toxicity. Given the recent interest in metal-chelation therapies for AD that remove metal from A beta leaving a metal-free A beta that can readily bind metals again, we believe that MT-2A might represent a different therapeutic approach as the metal exchange between MT and A beta leaves the A beta in a Zn-bound, relatively inert form.
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