Resistance of Cu(Aβ4-16) to Copper Capture by Metallothionein-3 Supports a Function for the Aβ4-42 Peptide as a Synaptic CuII Scavenger

• Published in: Angewandte Chemie 2016-07, Vol.128 (29), p.8375-8378
• Main Authors: Wezynfeld, Nina E., Stefaniak, Ewelina, Stachucy, Kinga, Drozd, Agnieszka, Płonka, Dawid, Drew, Simon C., Krężel, Artur, Bal, Wojciech
• Format: Article
• Language: English
• Subjects: Amyloid-beta-Peptide; Kupfer; Metalloproteine; Metallothionein; Zink
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201511968

Aβ4‐42 is a major species of Aβ peptide in the brains of both healthy individuals and those affected by Alzheimer's disease. It has recently been demonstrated to bind CuII with an affinity approximately 3000 times higher than the commonly studied Aβ1‐42 and Aβ1‐40 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 CuII from Aβ1‐40 when acting in its native Zn7MT‐3 form. This reaction is assumed to underlie the neuroprotective effect of Zn7MT‐3 against Aβ toxicity. In this work, we used the truncated model peptides Aβ1‐16 and Aβ4‐16 to demonstrate that the high‐affinity CuII complex of Aβ4‐16 is resistant to Zn7MT‐3 reactivity. This indicates that the analogous complex of the full‐length peptide Cu(Aβ4‐42) will not yield copper to MT‐3 in the brain, thus supporting the concept of a physiological role for Aβ4‐42 as a CuII scavenger in the synaptic cleft. Kupfersammlung: Aβ4‐42 ist eine Aβ‐Peptid‐Hauptspezies im Gehirn und bindet CuII mit einer etwa 3000‐mal höheren Affinität als die meist untersuchten Peptide Aβ1‐42 und Aβ1‐40. Zinkgebundenes Metallothionein‐3 (Zn7MT‐3) kann Kupfer (blau) nicht aus dem Hochaffinitäts‐CuII‐Komplex des Modellpeptids Aβ4‐16 herauslösen. Dieser Befund stützt die Annahme, dass Aβ4‐42 ein Rolle als CuII‐Fänger in der synaptischen Spalte spielt.