Resistance of Cu(Aß4-16) to Copper Capture by Metallothionein-3 Supports a Function for the Aß4-42 Peptide as a Synaptic Cu(II) Scavenger.

ABSTRACT

Aß4-42 is a major species of Aß peptide in the brains of both healthy individuals and those affected by Alzheimer's disease. It has recently been demonstrated to bind Cu(II) with an affinity approximately 3000 times higher than the commonly studied Aß1-42 and Aß1-40 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 Aß1-40 when acting in its native Zn7 MT-3 form. This reaction is assumed to underlie the neuroprotective effect of Zn7 MT-3 against Aß toxicity. In this work, we used the truncated model peptides Aß1-16 and Aß4-16 to demonstrate that the high-affinity Cu(II) complex of Aß4-16 is resistant to Zn7 MT-3 reactivity. This indicates that the analogous complex of the full-length peptide Cu(Aß4-42) will not yield copper to MT-3 in the brain, thus supporting the concept of a physiological role for Aß4-42 as a Cu(II) scavenger in the synaptic cleft.