Nuclear factor-κB activation by reactive oxygen species mediates voltage-gated K+ current enhancement by neurotoxic β-amyloid peptides in nerve growth factor-differentiated PC-12 cells and hippocampal neurones

Increased activity of plasma membrane K⁺ channels, leading to decreased cytoplasmic K⁺ concentrations, occurs during neuronal cell death. In the present study, we showed that the neurotoxic β-amyloid peptide Aβ_25-35 caused a dose-dependent (0.1-10 μM) and time-dependent (> 12 h) enhancement of both inactivating and non-inactivating components of voltage-dependent K⁺ (VGK) currents in nerve growth factor-differentiated rat phaeochromocytoma (PC-12) cells and primary rat hippocampal neurones. Similar effects were exerted by Aβ_1-42, but not by the non-neurotoxic Aβ_35-25 peptide. Aβ_25-35 and Aβ_1-42 caused an early (15-20 min) increase in intracellular Ca²⁺ concentration. This led to an increased production of reactive oxygen species (ROS), which peaked at 3 h and lasted for 24 h; ROS production seemed to trigger the VGK current increase as vitamin E (50 μM) blocked both the Aβ_25-35- and Aβ_1-42-induced ROS increase and VGK current enhancement. Inhibition of protein synthesis (cycloheximide, 1 μg/mL) and transcription (actinomycin D, 50 ng/mL) blocked Aβ_25-35-induced VGK current enhancement, suggesting that this potentiation is mediated by transcriptional activation induced by ROS. Interestingly, the specific nuclear factor-κB inhibitor SN-50 (5 μM), but not its inactive analogue SN-50M (5 μM), fully counteracted Aβ_1-42- or Aβ_25-35-induced enhancement of VGK currents, providing evidence for a role of this family of transcription factors in regulating neuronal K⁺ channel function during exposure to Aβ.