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

We found that the amyloid β peptide Aβ(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 Aβ(1-42) toxicity. The Aβ(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 μM. The [Cu²⁺]_cis-induced channel inhibition is fully reversible at low concentrations between 50 and 100 μM [Cu²⁺]_cis and partially reversible at 250 μM [Cu²⁺]_cis. The inhibitory effects of [Cu²⁺]_cis between 50 and 250 μM on the channel could not be reversed with addition of Cu²⁺-chelating agent clioquinol (CQ) at concentrations between 64 and 384 μM applied to the cis chamber. The effects of 200-250 μM [Cu²⁺]_cis on the burst and intraburst kinetic parameters were not fully reversible with either wash or 128 μM [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 Aβ(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 Aβ and PrP channel proteins linked to neurodegenerative diseases.