A beta(4-42) is the major subspecies of A beta peptides characterized by avid Cu(U) binding via the ATCUN/NTS motif. It is thought to be produced in vivo proteolytically by neprilysin, but in vitro experiments in the presence of Cu(II) ions indicated preferable formation of C-terminally truncated ATCUN/NTS species including CO(II)A beta(4-16), CO(II)A beta(4-9), and also CO(II)A beta(12-16), all with nearly femtomolar affinities at neutral pH. Such small complexes may serve as shuttles for copper clearance from extracellular brain spaces, on condition they could survive intracellular conditions upon crossing biological barriers. In order to ascertain such possibility, we studied the reactions of CO(II)A beta(4-16), CO(II)A beta(4-9), CO(II)A beta(12-16 ) and CO(II)A beta(1-16) with reduced glutathione (GSH) under aerobic and anaerobic conditions using absorption spectroscopy and mass spectrometry. We found CO(II)A beta(4-16) and CO(II)A beta(4-9) to be strongly resistant to reduction and concomitant formation of Cu(I)-GSH complexes, with reaction times similar to 10 h, while CO(II)A beta(12-16) was reduced within minutes and CO(II)A beta(1-16) within seconds of incubation. Upon GSH exhaustion by molecular oxygen, the CO(II)A beta complexes were reformed with no concomitant oxidative damage to peptides. These finding reinforce the concept of A beta(4-x) peptides as physiological trafficking partners of brain copper.