Cu2+-induced modification of the kinetics of Aβ(1-42) channels

We found that the amyloid beta peptide Abeta(1-42) is capable of interacting with membrane and forming heterogeneous ion channels in the absence of any added Cu2+ or biological redox agents that have been reported to mediate Abeta(1-42) toxicity. The Abeta(1-42)-formed cation channel was inhibited by Cu2+ in cis solution ([Cu2+](cis)) in a voltage- and concentration-dependent manner between 0 and 250 muM. The [Cu2+](cis)-induced channel inhibition is fully reversible at low concentrations between 50 and 100 muM [Cu2+](cis) and partially reversible at 250 muM [Cu2+](cis). The inhibitory effects of [Cu2+](cis) between 50 and 250 muM on the channel could not be reversed with addition of Cu2+-chelating agent clioquinol (CQ) at concentrations between 64 and 384 muM applied to the cis chamber. The effects of 200-250 muM [Cu2+](cis) on the burst and intraburst kinetic parameters were not fully reversible with either wash or 128 muM [CQ](cis). The kinetic analysis of the data indicate that Cu2+-induced inhibition was mediated via both desensitization and an open channel block mechanism and that Cu2+ binds to the histidine residues located at the mouth of the channel. It is proposed that the Cu2+-binding site of the Abeta(1-42)-formed channels is modulated with Cu2+ in a similar way to those of channels formed with the prion protein fragment PrP(106-126), suggesting a possible common mechanism for Cu2+ modulation of Abeta and PrP channel proteins linked to neurodegenerative diseases.