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 Cu(II) 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 Cu(II) from Aβ1-40 when acting in its native Zn7 MT-3 form. This reaction is assumed to underlie the neuroprotective effect of Zn7 MT-3 against Aβ toxicity. In this work, we used the truncated model peptides Aβ1-16 and Aβ4-16 to demonstrate that the high-affinity Cu(II) complex of Aβ4-16 is resistant to Zn7 MT-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 Cu(II) scavenger in the synaptic cleft.

Ab4-42 is amajor species of Ab peptide in the brains of both healthy individuals and those affected by Alzheimers disease.Ithas recently been demonstrated to bind Cu II with an affinity approximately 3000 times higher than the commonly studied Ab1-42 and Ab1-40 peptides,w hicha re implicated in the pathogenesis of Alzheimers disease.M etallothionein-3, ap rotein considered to orchestrate copper and zinc metabolism in the brain and provide antioxidant protection, was shown to extract Cu II from Ab1-40 when acting in its native Zn 7 MT-3 form. This reaction is assumed to underlie the neuroprotective effect of Zn 7 MT-3 against Ab toxicity.I nt his work, we used the truncated model peptides Ab1-16 and Ab4-16 to demonstrate that the high-affinity Cu II complex of Ab4-16 is resistant to Zn 7 MT-3 reactivity.T his indicates that the analogous complex of the full-length peptide Cu(Ab4-42) will not yield copper to MT-3 in the brain, thus supporting the concept of aphysiological role for Ab4-42 as aCu II scavenger in the synaptic cleft.