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

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.