Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 55, Issue 29, Pages 8235-8238Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201511968
Keywords
amyloid-beta peptides; copper; metalloproteins; metallothionein; zinc
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Funding
- National Science Centre of Poland [2014/15/B/ST5/05229]
- Ministry of Science and Higher Education [IP2012 018272]
- Centre for Preclinical Research and Technology (CePT) - European Regional Development Fund
- Innovative Economy, The National Cohesion Strategy of Poland
- [FT110100199]
- Australian Research Council [FT110100199] Funding Source: Australian Research Council
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A beta 4-42 isamajor species of A beta peptide in the brains of both healthy individuals and those affected by Alzheimer Is disease. It has recently been demonstrated to bind Cu-II with an affinity approximately 3000 times higher than the commonly studied A beta 1-42 and A beta 1-40 peptides, which are implicated in the pathogenesis of Alzheimer's disease. Metallothionein-3, a protein considered to orchestrate copper and zinc metabolism in the brain and provide antioxidant protection, was shown to extract Cu-II from A beta 1-40 when acting in its native Zn7MT-3 form. This reaction is assumed to underlie the neuroprotective effect of Zn7MT-3 against A beta toxicity. In this work, we used the truncated model peptides A beta 1-16 and A beta 4-16 to demonstrate that the high-affinity Cu-II complex of A beta 4-16 is resistant to Zn7MT-3 reactivity. This indicates that the analogous complex of the full-length peptide Cu(A beta 4-42) will not yield copper to MT-3 in the brain, thus supporting the concept of a physiological role for A beta 4-42 as a Cu-II scavenger in the synaptic cleft.
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