Aβ_4-42 is the major subspecies of Aβ peptides characterized by avid Cu(II) 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 Cu^IIAβ_4-16, Cu^IIAβ_4-9, and also Cu^IIAβ_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 Cu^IIAβ_4-16, Cu^IIAβ_4-9, Cu^IIAβ_12-16, and Cu^IIAβ_1-16 with reduced glutathione (GSH) under aerobic and anaerobic conditions using absorption spectroscopy and mass spectrometry. We found Cu^IIAβ_4-16 and Cu^IIAβ_4-9 to be strongly resistant to reduction and concomitant formation of Cu(I)-GSH complexes, with reaction times ∼10 h, while Cu^IIAβ_12-16 was reduced within minutes and Cu^IIAβ_1-16 within seconds of incubation. Upon GSH exhaustion by molecular oxygen, the Cu^IIAβ complexes were reformed with no concomitant oxidative damage to peptides. These finding reinforce the concept of Aβ_4-x peptides as physiological trafficking partners of brain copper.

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