Roles of Nuclear Factor κB in Neuronal Survival and Plasticity

Abstract

The transcription factor nuclear factor κB (NF‐κB) is moving to the forefront of the fields of apoptosis and neuronal plasticity because of recent findings showing that activation of NF‐κB prevents neuronal apoptosis in various cell culture and in vivo models and because NF‐κB is activated in association with synaptic plasticity. Activation of NF‐κB was first shown to mediate antiapoptotic actions of tumor necrosis factor in cultured neurons and was subsequently shown to prevent death of various nonneuronal cells. NF‐κB is activated by several cytokines and neurotrophic factors and in response to various cell stressors. Oxidative stress and elevation of intracellular calcium levels are particularly important inducers of NF‐κB activation. Activation of NF‐κB can interrupt apoptotic biochemical cascades at relatively early steps, before mitochondrial dysfunction and oxyradical production. Gene targets for NF‐κB that may mediate its anti‐apoptotic actions include the antioxidant enzyme manganese superoxide dismutase, members of the inhibitor of apoptosis family of proteins, and the calcium‐binding protein calbindin D28k. NF‐κB is activated by synaptic activity and may play important roles in the process of learning and memory. The available data identify NF‐κB as an important regulator of evolutionarily conserved biochemical and molecular cascades designed to prevent cell death and promote neuronal plasticity. Because NF‐κB may play roles in a range of neurological disorders that involve neuronal degeneration and/or perturbed synaptic function, pharmacological and genetic manipulations of NF‐κB signaling are being developed that may prove valuable in treating disorders ranging from Alzheimer’s disease to schizophrenia.