The native copper- and zinc-binding protein metallothionein blocks copper-mediated Abeta aggregation and toxicity in rat cortical neurons.
BACKGROUND
A major pathological hallmark of AD is the deposition of insoluble extracellular beta-amyloid (Abeta) plaques. There are compelling data suggesting that Abeta aggregation is catalysed by reaction with the metals zinc and copper.


RESULTS
We now report that the major human-expressed metallothionein (MT) subtype, MT-2A, is capable of preventing the in vitro copper-mediated aggregation of Abeta1-40 and Abeta1-42. This action of MT-2A appears to involve a metal-swap between Zn7MT-2A and Cu(II)-Abeta, since neither Cu10MT-2A or carboxymethylated MT-2A blocked Cu(II)-Abeta aggregation. Furthermore, Zn7MT-2A blocked Cu(II)-Abeta induced changes in ionic homeostasis and subsequent neurotoxicity of cultured cortical neurons.


CONCLUSIONS
These results indicate that MTs of the type represented by MT-2A are capable of protecting against Abeta aggregation and toxicity. Given the recent interest in metal-chelation therapies for AD that remove metal from Abeta leaving a metal-free Abeta that can readily bind metals again, we believe that MT-2A might represent a different therapeutic approach as the metal exchange between MT and Abeta leaves the Abeta in a Zn-bound, relatively inert form.
Chung
Roger S
RS
NeuroRepair Group, Menzies Research Institute, University of Tasmania, Hobart, Australia. Roger.Chung@utas.edu.au
Howells
Claire
C
Eaton
Emma D
ED
Shabala
Lana
L
Zovo
Kairit
K
Palumaa
Peep
P
Sillard
Rannar
R
Woodhouse
Adele
A
Bennett
William R
WR
Ray
Shannon
S
Vickers
James C
JC
West
Adrian K
AK
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003300:Copper / Q000378:metabolism*; D006801:Humans; D008668:Metallothionein / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D051381:Rats; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D012995:Solubility; D015032:Zinc / Q000378:metabolism*
D016229:Amyloid beta-Peptides; C491053:MT2A protein, human; D012967:Sodium Dodecyl Sulfate; D003300:Copper; D008668:Metallothionein; D015032:Zinc