Intracellular K⁺ plays a strategic role in cell survival acting as a negative regulator of some key enzymes involved in apoptosis, such as caspases and endonucleases, and by inhibiting cytochrome c-dependent apoptosome formation; furthermore blockade of K⁺ efflux inhibits cell proliferation and apoptotic cell death. As a matter of fact, an increased activity of plasma membrane K⁺ channels, leading to a decreased cytoplasmic K⁺ concentrations, occurs in different neurotoxicity models, such as during serum deprivation, staurosporine, ceramide or NMDA exposure, as well as upon lowering extracellular K⁺ concentrations ([K⁺]_e). Furthermore, alteration of K⁺ channel function in brain cells seems to play a relevant role also in the pathophysiology of Alzheimer Disease (AD); in fact, treatment for 3-24 hours with neurotoxic Aβ fragments enhances voltage-gated K⁺(VGK) channel activity in mouse SN-56 hybrid septal-neuroblastoma cells, in primary rat cerebellar granule cells, in cortical astrocytes and in microglial cells. Interestingly, the inhibition of K⁺ efflux, either by pharmacological tools or by increasing [K⁺]_e, fully prevented cell death induced by Aβ. Despite the large number of studies documenting an involvement of K⁺ channels in AD-related neuronal cell death, the molecular steps linking the exposure to neurotoxic events to the changes in K⁺ channel function remain controversial and poorly understood. Therefore, in the present study, we have evaluated the molecular mechanisms by which neurotoxic Aβs (Aβ_1-42, Aβ_25-35) enhance the expression of VGK currents in PC-12 cells differentiated by nerve growth factor (NGF) treatment and in primary rat hippocampal neurons. To this aim, we have evaluated the dependence of the enhanced K⁺ channel activity on extracellular Ca²⁺ availability, time-related production of ROS, protein synthesis, and transcriptional induction of nuclear factor-kappa B (NF-kB). The neurotoxic β-amyloid peptide Aβ_25-35 caused a dose- (0.1-10 μM) and time-dependent (>12 hours) enhancement of VGK currents in PC-12 cells and primary rat hippocampal neurons. Similar effects were exerted by Aβ_1-42, but not by the non-neurotoxic Aβ_25-35 peptide. Both inactivating and non-inactivating K⁺ currents components were potentiated upon neurotoxic Aβs treatment. Aβ_25-35 also caused an increased production of reactive oxygen species (ROS) which started at 20 minutes, peaked at 3 hours and lasted for 24 hours; this Aβ_25-35-induced ROS production was abolished upon the removal of extracellular Ca²⁺ from the incubation medium. Interestingly, ROS production seems to trigger VGK current increase since vitamin E (50 μM) completely abolished not only ROS production, but also Aβ_25-35-induced VGK currents enhancement. The protein synthesis inhibitor cycloheximide (1 μg/ml) and the transcription inhibitor 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 NF-kB inhibitor SN-50 (5 μM), but not its inactive analogue SN-50M (5 μM), fully counteracted the 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 Aβ exposure. Altogether, the present results suggest that cell death which follows neurotoxic Aβ peptides exposure of clonal and primary neurons involves an highly-coordinated sequence of events which include a Ca²⁺-dependent increased availability of ROS which, in turn, activates NF-kB transcription factors thus leading to the enhanced expression of VGK channels in the neuronal membrane. Given that an increased K⁺ channel function is likely to deplete intracellular K⁺, and that a decreased cytoplasmic K⁺ concentration represents an important prerequisite for cell death progression and execution mechanisms during exposure to several neurotoxic insults, the present result may be of considerable pathophysiological relevance for AD, as well as for other neurodegenerative disorders.