Signaling pathways that regulate NF-κB activity in neurons, and their possible involvement in the pathogenesis of neurodegenerative disorders. NF-κB in its inactive form is present in the cytosol as a three-subunit complex, with the prototypical components being p65 and p50 (transcription factor dimer) and IκBα (inhibitory subunit). NF-κB is activated by signals that activate IκB kinase (IKK), resulting in phosphorylation of IκBα; this targets IκBα for degradation in the proteosome and frees the p65-p50 dimer, which then translocates to the nucleus and binds to consensus κB sequences in the enhancer region of κB-responsive genes. Diverse signals can induce NF-κB activation, including TNF-α, sAPPα, NGF, and glutamate; increases in levels of intracellular Ca2+ and reactive oxygen species such as H2O2 can be potent activators of NF-κB. NF-κB induces the expression of several different genes that promote neuron survival, including those encoding manganese superoxide dismutase (Mn-SOD), inhibitor-of-apoptosis proteins (IAPs), Bcl-2, and calbindin. Several signals that inhibit NF-κB activity are generated in neurons undergoing apoptosis; examples include prostate apoptosis response-4 (Par-4) and the lipid peroxidation product 4-hydroxynonenal (HNE). NF-κB is modulated by signals emanating from the endoplasmic reticulum (ER) and mitochondria (MIT). AP1, activator protein-1; GRP78, glucose-regulated protein-78; JUNK, Jun NH2-terminal kinase; PKG, cGMP-dependent protein kinase.