NF-κB in Brain Diseases 305 6 Role of NF-κB in Brain Diseases Because NF-κB plays many important roles, it is not surprising that dysregulation of NF-κB signaling is involved in the pathogenesis of a number of human diseases. Except those resulting from mutations affecting components of the NF-κB signaling pathway reviewed by (Courtois and Smahi, 2006), the mechanisms by which NF- κB is involved in disease pathogenesis appear to be complicated, requiring future investigation. The diseases in which abnormal NF-κB regulation has been reported to play significant roles include atherosclerosis, AIDS, tumors, diabetes, heart dis- eases, muscular dystrophy, rheumatoid arthritis, inflammatory bowel diseases, bone resorption, and some neurodegenerative diseases reviewed by (Kumar et al., 2004). Investigation of the roles of NF-κB in brain diseases is just beginning, focusing mainly on acute and chronic neurodegeneration. Although the exact roles of NF-κB in these brain diseases are not yet known, these roles certainly deserve thorough investigation in the near future. Hence, these studies are reviewed in this section. 6.1 Role of NF-κB in Ischemic and Traumatic Brain Injury NF-κB is dramatically activated in brain tissue in rodent models of stroke or car- diac arrest. Transient global forebrain ischemia causes NF-κB activation in CA1 hippocampal neurons (Clemens et al., 1997). A delayed increase in NF-κB activa- tion in association with reactive glial cells was also observed several days after focal ischemia/reperfusion (Gabriel et al., 1999). Studies of mice lacking the p50 subunit of NF-κB suggest that, overall, NF-κB activation enhances ischemic neuronal death, but its effects differ among different cell types (Schneider et al., 1999). NF-κB acti- vation in microglia promotes ischemic neuronal degeneration, whereas activation of NF-κB in neurons may increase their survival after a stroke. In cultured neuronal cells, activation of NF-κB protects them against excitotoxic and metabolic insults relevant to the pathogenesis of stroke, including glucose deprivation and exposure to glutamate (Cheng et al., 1994; Yu et al., 1999). The cortical and striatal neu- rons of mice that fail to induce the κB-responsive Mn-superoxide dismutase (SOD) gene due to lack of TNF-α receptors are more vulnerable to focal ischemic injury (Schmidt-Ullrich et al., 1996). The neuroprotective effect of endogenous TNF-α is likely mediated by NF-κB activation in neurons, because mice lacking p50 and mice treated with κB decoy DNA exhibit increased vulnerability of hippocampal neurons to excitotoxicity (Yu et al., 1999). The IκB kinase complex (IKK) is also activated in a mouse model of stroke and appears to play a key function in ischemic brain damage (Herrmann et al., 2005). Inhibition of neuronal IKK activity in trans- genic mice that either lack IKK2 or express a dominant inhibitor of I KK reduces infarct size markedly. In contrast, constitutive activation of IKK2 enlarges the infarct size (Herrmann et al., 2005). The postischemic inflammatory response is critical to the consequence of stroke, and this response is mainly mediated by NF-κB signal- ing (reviewed by (Zheng and Yenari, 2004)). Therefore, NF-κB may be a potential molecular target for ischemic stroke therapy. 306 C X. Gong NF-κB activation also occurs in the cerebral cortex within hours of traumatic brain injury in rats, and this activation becomes maximal within the first 24 h (Nonaka et al., 1999; Sanz et al., 2002). Immunohistochemical staining indicates an increase of p65 level i n the axons first and, subsequently, in neuronal cell bodies. The increased p65 level also occurs in the neighboring microglia and astrocytes. This increase in p65 immunoreactivity persists for many months, especially in the margins of the progressively enlarging ventricle, suggesting a role for NF-κBina prolonged inflammatory process. In addition, expression of IκBα is also observed in astrocytes and microglial cells of the corpus callosum in traumatic brain injury at the time of NF-κB activation (Sanz et al., 2002). 6.2 Role of NF-κB in Seizures In laboratory animals, NF-κB activity is rapidly increased in hippocampal neurons within 4–6 h after kainate-induced seizures, which is followed by a delayed and sustained NF-κB activation in glial cells (Yu et al., 1999). Intraventricular infusion of κB decoy DNA prior to administration of kainate causes a significant increase in the extent of neuronal death, suggesting an excitoprotective role for seizure-induced neuronal NF-κB activation. In mice lacking the p50 subunit of NF-κB, which is required for the vast majority of κB DNA-binding activity in the hippocampus, seizure-induced neuronal degeneration is greater than in control mice (Yu et al., 1999). Cultured hippocampal neurons from p50-deficient mice exhibit enhanced elevation of intracellular calcium levels upon exposure to glutamate and are more vulnerable to excitotoxicity as compared with neurons from wild-type mice. These studies suggest that the p50 subunit of NF-κB plays a major role in protecting neurons against excitotoxicity. Excitotoxic and ischemic injury to neurons is partially mediated by dysregulation of cellular calcium homeostasis, resulting in a prolonged elevation of intracellular calcium levels. Neuronal NF-κB activation can stabilize intracellular calcium con- centrations under ischemia-like conditions (Barger et al., 1995; Barger and Mattson, 1996), possibly via induction of several different genes, including those encoding calcium-binding proteins and glutamate receptor (Cheng et al., 1994; Furukawa and Mattson, 1998; Gary et al., 2000). 6.3 Role of NF-κB in Alzheimer Disease (AD) Recent studies suggest that dysregulation of NF-κB signaling might be involved in the pathogenesis of AD. NF-κB immunoreactivity is found especially in and around the early senile plaques in AD brain, whereas mature plaques show mainly reduced NF-κB activity (Kaltschmidt et al., 1999). Several reports suggest that amyloid β (Aβ) peptide can activate NF-κB in neurons, suggesting a plausible mechanism by which Aβ may act in AD (Barger et al., 1995). Actually, elevation and activation of p65 and p50 subunits of NF-κB have been observed in AD brain (Yan et al., 1995; NF-κB in Brain Diseases 307 Boissiere et al., 1997; Kaltschmidt et al., 1997). Activation of NF-κB protects hip- pocampal neurons against oxidative stress-induced apoptosis (Mattson et al., 1997). On the other hand, inhibition of NF-κB potentiates Aβ-mediated neuronal apoptosis (Kaltschmidt et al., 1999). The proapoptotic protein prostate–apoptosis response- 4 (Par-4), which is implicated in AD, kills neurons partially by inhibiting NF-κB activity (Guo et al., 1998a). Interestingly, expression of IκB-α,IκB-γ and its pre- cursor, p105, are also increased in AD brain (Yoshiyama et al., 2001; Huang et al., 2005), and the increased IκBα expression is in a distribution that corresponds to the neurofibrillary pathology of AD (Yoshiyama et al., 2001). It is interesting that a low dose (0.1 μM) of Aβ is able to activate NF-κB and to protect against a high cytotoxic dose (10 μM) of Aβ (Kaltschmidt et al., 1999). This finding actually led to the discovery of an essential role for NF-κB in precon- ditioning (Blondeau et al., 2001; Ravati et al., 2001). The underlying mechanisms might be similar to a process described by Baltimore (1988) as intracellular immu- nization against virus infection. Overexpression of transdominant IκB-α completely abolishes the preconditioning effect of NF-κB. General evidence suggests that con- stitutive NF-κB activity is essential for neuronal survival (Bhakar et al., 2002). This protective role might be perturbed in AD brain, for example, by oxidative stress. Activation of neuronal NF-κB in AD may be a neuroprotective response, but activation of NF-κB in glial cells may mediate the production of proinflammatory cytokine and nitric oxide associated with the amyloid and neurofibrillary pathol- ogy in AD (Chen et al., 2005; Ho et al., 2005). NF-κB might also play a role in amyloidogenesis of AD, because the enhancer region 5 to the APP gene contains NF-κB–binding sites, and expression of APP can be induced by NF-κB (Grilli et al., 1996). A recent report suggests that NF-κB activation may also mediate sAPPα release (Choi et al., 2006). Mutations of the presenilin-1 gene are the major cause of inherited early-onset AD. Presenilin-1 mutations impair the ability of neurons to induce NF-κB activation under conditions of oxidative stress in the pathogenesis of AD (Guo et al., 1998b). An abnormal NF-κB response occurs in neurons expressing mutant presenilin-1, such that it is activated rapidly but then drops to a very low level for a prolonged period. Transgenic mice with presenilin mutation exhibit impaired NF-κB activation in response to exposure to trimethyltin (Kassed et al., 2003). 6.4 Role of NF-κB in Parkinson’s Disease (PD) and Huntington’s Disease (HD) PD and HD are age-related movement disorders that involve degeneration of dopaminergic neurons in the substantia nigra and medium spiny neurons in the stria- tum, respectively. It is striking that there is a seventyfold increase in the percentage of dopaminergic neurons with nuclear immunoreactive NF-κB p65, which indicates NF-κB activation, in the substantia nigra of PD patients as compared to age-matched controls (Hunot et al., 1997). This observation suggests a role of NF-κB activa- tion in PD. Increased levels of oxidative stress and mitochondrial dysfunction are 308 C X. Gong implicated in the pathogenesis of both PD and HD (Rao and Balachandran, 2002; Jenner, 2003). NF-κB activity increased in affected neurons in the substantia nigra and striatum may represent an early protective response to ongoing oxidative stress and mitochondrial dysfunction (Browne et al., 1999; Jenner, 2003). Consistent with this is that an NF-κB inhibitor increases the vulnerability of dopaminergic neurons to Parkinsonian neurotoxin 6-hydroxydopamine (Park et al., 2004). Mice lacking the p50 subunit of NF-κB exhibit increased damage to striatal neurons and worsened motor dysfunction after administration of the mitochondrial toxin 3-nitropropionic acid in an HD animal model (Yu et al., 2000). Levels of Mn-SOD are increased in response to 3-nitropropionic acid in striatal cells of wild-type mice, but not in striatal cells of mice lacking p50, suggesting a pivotal role of NF-κB in this neuroprotective response. However, NF-κB activation may also promote the death of neurons under conditions such as oxidative and metabolic stress that often occur in neurodegener- ative diseases (Schneider et al., 1999; Gill and Windebank, 2000). In a neuronal cell line, mutant huntingtin is found to activate NF-κB, and blockage of the NF-κB acti- vation reduces the toxicity of the mutant huntingtin (Khoshnan et al., 2004). What determines whether NF-κB activation is beneficial or detrimental for neurons in the context of neurodegenerative disorders is barely understood, but it likely involves regulatory elements that determine whether NF-κB increases the expression of pro- or antiapoptotic genes. Microglial activation has been shown to contribute to neu- ronal death in PD, and this activation may be mediated by the NF-κB/p38 MAPK pathway (Wilms et al., 2003). 6.5 Role of NF-κB in Multiple Sclerosis Multiple sclerosis is a chronic autoimmune disease of the CNS, in which myelin and myelin-forming oligodendrocytes become the target of an inflammatory response, leading to their depletion. Although the molecular mechanism of oligodendrocyte depletion is not well understood, increased levels of TNF-α and IL-1β transcripts and activation of NF-κB have been observed in active multiple sclerosis lesions (Gveric et al., 1998; Bonetti et al., 1999). Both TNF-α and IL-1β are NF-κB– regulated proinflammatory cytokines that also cause apoptosis of oligodendrocytes (Selmaj and Raine, 1988). In CNS glial cells treated with proinflammatory cytokine, inhibition of NF-κB transactivation by IL-4 protects differentiating oligodendrocyte progenitors (Paintlia et al., 2006). This observation further supports a role of NF- κB in the pathogenesis of multiple sclerosis. Theiler’s virus infection in the CNS induces a demyelinating disease very similar to multiple sclerosis. This infection directly induces proinflammatory cytokines in primary astrocytes via NF-κB activa- tion (Palma et al., 2003), suggesting that NF-κB is critical for the development of immune-mediated demyelination. Genetic studies demonstrate that inhibitors of the NF-κB cascade comprise prime candidate genes predisposing to multiple sclerosis (Miterski et al., 2002). NF-κB also regulates transcription of myelin basic protein gene in oligodendroglioma cells (Huang et al., 2002). NF-κB in Brain Diseases 309 7NF-κB Signaling Pathway as a Potential Therapeutic Target The involvement of NF-κB in several vital biological functions and in the patho- genesis of many human diseases suggests that it could be an important target for therapeutic intervention. The first evidence that NF-κB pathways could be inhib- ited came from studies of IκB-α mutant that could not be phosphorylated by IKK and thus not degraded by proteasome (Ghosh et al., 1998). This IκB-α mutant sequesters NF-κB in the cytoplasm and thus prevents the induction of specific NF-κB target genes. Delivering this IκB-α suppressor mutant by adenoviral vec- tors has been effective in rheumatoid arthritis models (Bondeson et al., 1999) and in reducing the resistance of tumors to chemotherapy in a mouse model (Wang et al., 1999). Targeting NF-κB for treating diseases has recently been reviewed elsewhere (Monaco and Paleolog, 2004; Panwalker et al., 2004;Verma,2004). The emerging data described above suggest that NF-κB plays important roles in cellular response to injury of the CNS in both acute and chronic neurodegener- ative conditions. Therefore, the NF-κB pathway is no doubt a potential important target for therapeutic intervention of neurological disorders. Drugs targeting NF-κB in the CNS of animal models of neurodegenerative conditions are just beginning to be tested. In a rat model of embolic focal cerebral ischemia, bortezomib (a potent and selective inhibitor of proteasome) was found to reduce adverse cerebrovascu- lar events, including secondary thrombosis, inflammatory response and blood–brain barrier, and hence reduce infarct volume and neurological functional deficits when administrated within 4 h after stroke onset. These protective actions are mediated by blocking endothelial NF-κB (Zhang et al., 2006). In a mouse model of stroke, a selective small molecule inhibitor of IKK reduces the infarct volume and cell death in a therapeutic window of 4.5 h (Herrmann et al., 2005). A natural green tea constituent, (–)-epigallocatechin-5-gallate, can limit brain inflammation and reduce neuronal damage via inhibiting NF-κB overactivation in an animal model of autoim- mune encephalomyelitis, which opens a new therapeutic avenue for inflammatory brain diseases (Aktas et al., 2004). Recent studies have demonstrated that a number of pharmacological agents act via their activities to inhibit NF-κB. The immunosuppressive and anti-inflammatory actions of glucocorticosteroids are mediated in part by the induction of IκB-α synthesis (Yamamoto and Gaynor, 2001). Nonsteroidal anti-inflammatory drugs also inhibit endotoxin- and cytokine-induced nuclear translocation of NF-κBby preventing IκB-α phosphorylation and degradation. Some naturally occurring and synthetic inhibitors of ubiquitin-proteasome also block NF-κB activation by pre- venting IκB degradation (Adams et al., 2000). Several pharmaceutical companies are now developing novel specific inhibitors of IKK (Haefner, 2002). Because NF-κB is involved in a variety of neuronal functions and memory processing, use of any agents targeting the NF-κB pathway in brain diseases is com- plicated and warrants extensive studies. In general, activation of NF-κB in neurons protects them against degeneration, but activation of NF-κB in microglia promotes neuronal degeneration. Hence, ideal agents to target NF-κB should be cell type- selective in their actions. For example, inhibitors of NF-κB that selectively target 310 C X. Gong microglial cells may suppress damaging neural inflammation without affecting the normal functions of NF-κB in neurons. Selecting such cell type-selective agents will be a major focus of future research. Acknowledgments The author is grateful to Drs. K. Iqbal and I. Grundke-Iqbal of our insti- tute and Dr. X. Zhu of the Institute of Pathology, Case Western Reserve University, Cleveland, OH, for critical reading of the manuscript, to Ms. M. Marlow of our institute for help in edit- ing this manuscript, and to Ms. J. Murphy and Ms. S. Warren for secretarial assistance. Studies in my laboratory are supported in part by funds from the New York State Office of Mental Retardation and Developmental Disabilities, and grants from the NIH (R01 AG16760, R01 AG027429), the Alzheimer’s Association, Chicago, IL (IIRG-05-13095), and the Li Foundation, Inc., New York, NY. References Adams J, Palombella VJ, Elliott PJ (2000) Proteasome inhibition: a new strategy in cancer treatment. Invest New Drugs 18:109–121 Aggarwal BB (2004) Nuclear factor-kappaB: the enemy within. Cancer Cell 6:203–208 Akama KT, Albanese C, Pestell RG, Van Eldik LJ (1998) Amyloid beta-peptide stimulates nitric oxide production in astrocytes through an NFkappaB-dependent mechanism. Proc Natl Acad Sci USA 95:5795–5800 Aktas O, Prozorovski T, Smorodchenko A, Savaskan NE, Lauster R et al (2004) Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotec- tion in autoimmune encephalomyelitis. J Immunol 173:5794–5800 Albensi BC, Mattson MP (2000) Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity. Synapse 35:151–159 Baltimore D (1988) Gene therapy intracellular immunization. Nature 335:395–396 Barger SW, Horster D, Furukawa K, Goodman Y, Krieglstein J et al (1995) Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation. Proc Natl Acad Sci USA 92:9328–9332 Barger SW, Mattson MP (1996) Induction of neuroprotective kappa B-dependent transcription by secreted forms of the Alzheimer’s beta-amyloid precursor. Brain Res Mol Brain Res 40: 116–126 Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK et al (2002) Control of synaptic strength by glial TNFalpha. Science 2955:2282–2285 Beg AA, Baltimore D (1996) An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 274:782–784 Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D (1995) Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 376: 167–170 Bhakar AL, Tannis LL, Zeindler C, Russo MP, Jobin C et al (2002) Constitutive nuclear factor- kappa B activity is required for central neuron survival. J Neurosci 22:8466–8475 Blondeau N, Widmann C, Lazdunski M, Heurteaux C (2001) Activation of the nuclear factor- kappaB is a key event in brain tolerance. J Neurosci 21:4668–4677 Boissiere F, Hunot S, Faucheux B, Duyckaerts C, Hauw JJ, Agid Y et al (1997) Nuclear translo- cation of NF-kappaB in cholinergic neurons of patients with Alzheimer’s disease. Neuroreport 8:2849–2852 Bondeson J, Foxwell B, Brennan F, Feldmann M (1999) Defining therapeutic targets by using adenovirus: blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. Proc Natl Acad Sci USA 96:5668–5673 NF-κB in Brain Diseases 311 Bonetti B, Stegagno C, Cannella B, Rizzuto N, Moretto G et al (1999) Activation of NF-kappaB and c-jun transcription factors in multiple sclerosis lesions. Implications for oligodendrocyte pathology. Am J Pathol 155:1433–1438 Browne SE, Ferrante RJ, Beal MF (1999) Oxidative stress in Huntington’s disease. Brain Pathol 9:147–163 Bui NT, Livolsi A, Peyron JF, Prehn JH (2001) Activation of nuclear factor kappaB and Bcl-x survival gene expression by nerve growth factor requires tyrosine phosphorylation of IkappaBalpha. J Cell Biol 152:753–764 Burkly L, Hession C, Ogata L, Reilly C, Marconi LA et al (1995) Expression of relB is required for the development of thymic medulla and dendritic cells. Nature 373:531–536 Caamano JH, Rizzo CA, Durham SK, Barton DS, Raventos-Suarez C et al (1998) Nuclear factor (NF)-kappa B2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses. J Exp Med 187:185–196 Carter BD, Kaltschmidt C, Kaltschmidt B, Offenhauser N, Bohm-Matthaei R et al (1996) Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75. Science 272:542–545 Carter AB, Knudtson KL, Monick MM, Hunninghake GW (1999) The p38 mitogen-activated pro- tein kinase is required for NF-kappaB-dependent gene expression. The role of TATA-binding protein (TBP). J Biol Chem 274:30858–30863 Cauley K, Verma IM (1994) Kappa B enhancer-binding complexes that do not contain NF-kappa B are developmentally regulated in mammalian brain. Proc Natl Acad Sci USA 91:390–394 Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S et al (2005) SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem 280:40364–40374 Cheng B, Christakos S, Mattson MP (1994) Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron 12:139–153 Choi S, Kim JH, Roh EJ, Ko MJ, Jung JE et al (2006) Nuclear factor-kappa B activated by capacita- tive Ca2+ entry enhances muscarinic receptor-mediated sAPPalpha release in SH-SY5Y cells. J Biol Chem 281:12722–12728 Clemens JA, Stephenson DT, Smalstig EB, Dixon EP, Little SP (1997) Global ischemia acti- vates nuclear factor-kappa B in forebrain neurons of rats. Stroke 28:1073–1080. discussion 1080–1081 Courtois G, Smahi A (2006) NF-kappaB-related genetic diseases. Cell Death Differ 13:843–851 Dajee M, Lazarov M, Zhang JY, Cai T, Green CL et al (2003) NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421:639–643 DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M (1997) A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 388:548–554 Digicaylioglu M, Lipton SA (2001) Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 412:641–647 Duran A, Diaz-Meco MT, Moscat J (2003) Essential role of RelA Ser311 phosphorylation by zetaPKC in NF-kappaB transcriptional activation. EMBO J 22:3910–3918 Ernst MK, Dunn LL, Rice NR (1995) The PEST-like sequence of I kappa B alpha is responsible for inhibition of DNA binding but not for cytoplasmic retention of c-Rel or RelA homodimers. Mol Cell Biol 15:872–882 Fan C, Li Q, Ross D, Engelhardt JF (2003) Tyrosine phosphorylation of I kappa B alpha activates NF kappa B through a redox-regulated and c-Src-dependent mechanism following hypoxia/reoxygenation. J Biol Chem 278:2072–2080 Franzoso G, Bours V, Park S, Tomita-Yamaguchi M, Kelly K et al (1992) The candidate oncopro- tein Bcl-3 is an antagonist of p50/NF-kappa B-mediated inhibition. Nature 359:339–342 Freudenthal R, Locatelli F, Hermitte G, Maldonado H, Lafourcade C et al (1998) Kappa-B like DNA-binding activity is enhanced after spaced training that induces long-term memory in the crab Chasmagnathus. Neurosci Lett 242:143–146 312 C X. Gong Furukawa K, Mattson MP (1998) The transcription factor NF-kappaB mediates increases in cal- cium currents and decreases in NMDA- and AMPA/kainate-induced currents induced by tumor necrosis factor-alpha in hippocampal neurons. J Neurochem 70:1876–1886 Gabriel C, Justicia C, Camins A, Planas AM (1999) Activation of nuclear factor-kappaB in the rat brain after transient focal ischemia. Brain Res Mol Brain Res 65:61–69 Gary DS, Sooy K, Chan SL, Christakos S, Mattson MP (2000) Concentration- and cell type- specific effects of calbindin D28k on vulnerability of hippocampal neurons to seizure-induced injury. Brain Res Mol Brain Res 75:89–95 Gerondakis S, Strasser A, Metcalf D, Grigoriadis G, Scheerlinck JY (1996) Rel-deficient T cells exhibit defects in production of interleukin 3 and granulocyte-macrophage colony-stimulating factor. Proc Natl Acad Sci USA 93:3405–3409 Ghosh S, May MJ, Kopp EB (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260 Gill JS, Windebank AJ (2000) Ceramide initiates NFkappaB-mediated caspase activation in neuronal apoptosis. Neurobiol Dis 7:448–461 Gilmore TD, Kalaitzidis D, Liang MC, Starczynowski DT (2004) The c-Rel transcription factor and B-cell proliferation: a deal with the devil. Oncogene 23:2275–2286 Grilli M, Goffi F, Memo M, Spano P (1996) Interleukin-1beta and glutamate activate the NF- kappaB/Rel binding site from the regulatory region of the amyloid precursor protein gene in primary neuronal cultures. J Biol Chem 271:15002–15007 Grilli M, Ribola M, Alberici A, Valerio A, Memo M et al (1995) Identification and characterization of a kappa B/Rel binding site in the regulatory region of the amyloid precursor protein gene. J Biol Chem 270:26774–26777 Grumont RJ, Rourke IJ, Gerondakis S (1999) Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes Dev 13:400–411 Guerrini L, Blasi F, Denis-Donini S (1995) Synaptic activation of NF-kappa B by glutamate in cerebellar granule neurons in vitro. Proc Natl Acad Sci USA 92:9077–9081 Guo Q, Fu W, Xie J, Luo H, Sells SF et al (1998a) Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Nat Med 4:957–962 Guo Q, Robinson N, Mattson MP (1998b) Secreted beta-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-kappaB and stabilization of calcium homeostasis. J Biol Chem 273:12341–12351 Gveric D, Kaltschmidt C, Cuzner ML, Newcombe J (1998) Transcription factor NF-kappaB and inhibitor I kappaBalpha are localized in macrophages in active multiple sclerosis lesions. J Neuropathol Exp Neurol 57:168–178 Haefner B (2002) NF-kappa B: arresting a major culprit in cancer. Drug Discov Today 7:653–663 Heron E, Deloukas P, van Loon AP (1995) The c omplete exon-intron structure of the 156-kb human gene NFKB1, which encodes the p105 and p50 proteins of transcription factors NF-kappa B and I kappa B-gamma: implications for NF-kappa B-mediated signal transduction. Genomics 30:493–505 Herrmann O, Baumann B, de Lorenzi R, Muhammad S, Zhang W et al (2005) IKK mediates ischemia-induced neuronal death. Nat Med 11:1322–1329 Ho GJ, Drego R, Hakimian E, Masliah E (2005) Mechanisms of cell signaling and inflammation in Alzheimer’s disease. Curr Drug Targets Inflamm Allergy 4:247–256 Huang Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2005) NF-kappaB precursor, p105, and NF- kappaB inhibitor, IkappaBgamma, are both elevated in Alzheimer disease brain. Neurosci Lett 373:115–118 Huang TT, Miyamoto S (2001) Postrepression activation of NF-kappaB requires the amino- terminal nuclear export signal specific to IkappaBalpha. Mol Cell Biol 21:4737–4747 Huang CJ, Nazarian R, Lee J, Zhao PM, Espinosa-Jeffrey A et al (2002) Tumor necrosis factor modulates transcription of myelin basic protein gene through nuclear factor kappa B in a human oligodendroglioma cell line. Int J Dev Neurosci 20:289–296 NF-κB in Brain Diseases 313 Hunot S, Brugg B, Ricard D, Michel PP, Muriel MP et al (1997) Nuclear translocation of NF- kappaB is increased in dopaminergic neurons of patients with parkinson disease. Proc Natl Acad Sci USA 94:7531–7536 Huxford T, Malek S, Ghosh G (1999) Structure and mechanism in NF-kappaB/IkappaB signalling. Cold Spring Harb Symp Quant Biol LXIV:533–540 Inoue J, Kerr LD, Kakizuka A, Verma IM (1992) I kappa B gamma, a 70 kd protein identical to the C-terminal half of p110 NF-kappa B: a new member of the I kappa B family. Cell 68: 1109–1120 Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53(Suppl 3):S26–S36. discussion S36–38 Kaltschmidt C, Kaltschmidt B, Baeuerle PA (1993) Brain synapses contain inducible forms of the transcription factor NF-kappa B. Mech Dev 43:135–147 Kaltschmidt C, Kaltschmidt B, Baeuerle PA (1995) Stimulation of ionotropic glutamate recep- tors activates transcription factor NF-kappa B in primary neurons. Proc Natl Acad Sci USA 92:9618–9622 Kaltschmidt C, Kaltschmidt B, Neumann H, Wekerle H, Baeuerle PA (1994) Constitutive NF- kappa B activity in neurons. Mol Cell Biol 14:3981–3992 Kaltschmidt B, Linker RA, Deng J, Kaltschmidt C (2002) Cyclooxygenase-2 is a neuronal target gene of NF-kappaB. BMC Mol Biol 3:16 Kaltschmidt B, Ndiaye D, Korte M, Pothion S, Arbibe L et al (2006) NF-kappaB regulates spatial memory formation and synaptic plasticity through protein kinase A/CREB signaling. Mol Cell Biol 26:2936–2946 Kaltschmidt B, Uherek M, Volk B, Baeuerle PA, Kaltschmidt C (1997) Transcription factor NF- kappaB is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques from patients with Alzheimer disease. Proc Natl Acad Sci USA 94:2642–2647 Kaltschmidt B, Uherek M, Wellmann H, Volk B, Kaltschmidt C (1999) Inhibition of NF-kappaB potentiates amyloid beta-mediated neuronal apoptosis. Proc Natl Acad Sci USA 96:9409–9414 Kaltschmidt B, Widera D, Kaltschmidt C (2005) Signaling via NF-kappaB in the nervous system. Biochim Biophys Acta 1745:287–299 Karin M, Takahashi T, Kapahi P, Delhase M, Chen Y et al (2001) Oxidative stress and gene expression: the AP-1 and NF-kappaB connections. Biofactors 15:87–89 Kassed CA, Butler TL, Navidomskis MT, Gordon MN, Morgan D et al (2003) Mice expressing human mutant presenilin-1 exhibit decreased activation of NF-kappaB p50 in hippocampal neurons after injury. Brain Res Mol Brain Res 110:152–157 Kassed CA, Butler TL, Patton GW, Demesquita DD, Navidomskis MT et al (2004) Injury- induced NF-kappaB activation in the hippocampus: implications for neuronal survival. FASEB J 18:723–724 Kassed CA, Willing AE, Garbuzova-Davis S, Sanberg PR, Pennypacker KR (2002) Lack of NF- kappaB p50 exacerbates degeneration of hippocampal neurons after chemical exposure and impairs learning. Exp Neurol 176:277–288 Kato T Jr, Delhase M, Hoffmann A, Karin M (2003) CK2 Is a C-Terminal IkappaB Kinase Responsible for NF-kappaB Activation during the UV Response. Mol Cell 12:829–839 Khoshnan A, Ko J, Watkin EE, Paige LA, Reinhart PH et al (2004) Activation of the IkappaB kinase complex and nuclear factor-kappaB contributes to mutant huntingtin neurotoxicity. J Neurosci 24:7999–8008 Kim BY, Gaynor RB, Song K, Dritschilo A, Jung M (2002) Constitutive activation of NF-kappaB in Ki-ras-transformed prostate epithelial cells. Oncogene 21:4490–4497 Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH et al (2000) The R elA NF- kappaB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells. Oncogene 19:5498–5506 Kontgen F, Grumont RJ, Strasser A, Metcalf D, Li R et al (1995) Mice lacking the c-rel proto- oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev 9:1965–1977 314 C X. Gong Korner M, Rattner A, Mauxion F, Sen R, Citri Y (1989) A brain-specific transcription activator. Neuron 3:563–572 Kovacs AD, Chakraborty-Sett S, Ramirez SH, Sniderhan LF, Williamson AL et al (2004) Mechanism of NF-kappaB inactivation induced by survival signal withdrawal in cerebellar granule neurons. Eur J Neurosci 20:345–352 Kraus J, Borner C, Giannini E, Hollt V (2003) The role of nuclear factor kappaB in tumor necro- sis factor-regulated transcription of the human mu-opioid receptor gene. Mol Pharmacol 64: 876–884 Kucharczak J, Simmons MJ, Fan Y, Gelinas C (2003) To be, or not to be: NF-kappaB is the answer– role of Rel/NF-kappaB in the regulation of apoptosis. Oncogene 22:8961–8982. Erratum in: Oncogene. 2004 23:8858 Kumar A, Takada Y, Boriek AM, Aggarwal BB (2004) Nuclear factor-kappaB: its role in health and disease. J Mol Med 82:434–448 Li N, Karin M (1998) Ionizing radiation and short wavelength UV activate NF-kappaB through two distinct mechanisms. Proc Natl Acad Sci USA 95:13012–13017 Liou HC, Jin Z, Tumang J, Andjelic S, Smith KA et al (1999) c-Rel is crucial for lymphocyte proliferation but dispensable for T cell effector function. Int Immunol 11:361–371 Lipsky RH, Xu K, Zhu D, Kelly C, Terhakopian A et al (2001) Nuclear factor kappaB is a critical determinant in N-methyl-D-aspartate receptor-mediated neuroprotection. J Neurochem 78:254–264 Liu H, Yu W, Liou LY, Rice AP (2003) Isolation and characterization of the human DC-SIGN and DC-SIGNR promoters. Gene 313:149–159 Lorimer DD, Matkowskj K, Benya RV (1997) Cloning, chromosomal location, and transcriptional regulation of the human galanin-1 receptor gene (GALN1R). Biochem Biophys Res Commun 241:558–564 Madrigal JL, Moro MA, Lizasoain I, Lorenzo P, Castrillo A et al (2001) Inducible nitric oxide synthase expression in brain cortex after acute restraint stress is regulated by nuclear factor kappaB-mediated mechanisms. J Neurochem 76:532–538 Maggirwar SB, Sarmiere PD, Dewhurst S, Freeman RS (1998) Nerve growth factor-dependent activation of NF-kappaB contributes to survival of sympathetic neurons. J Neurosci 18: 10356–10365 Malek S, Huxford T, Ghosh G (1998) Ikappa Balpha functions through direct contacts with the nuclear localization signals and the DNA binding sequences of NF-kappaB. J Biol Chem 273:25427–25435 Malinin NL, Boldin MP, Kovalenko AV, Wallach D (1997) MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature 385:540–544 Mattson MP, Goodman Y, Luo H, Fu W, Furukawa K (1997) Activation of NF-kappaB pro- tects hippocampal neurons against oxidative stress-induced apoptosis: evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration. J Neurosci Res 49:681–697 Mayo MW, Norris JL, Baldwin AS (2001) Ras regulation of NF-kappa B and apoptosis. Methods Enzymol 333:73–87 Meberg PJ, Kinney WR, Valcourt EG, Routtenberg A (1996) Gene expression of the transcription factor NF-kappa B in hippocampus: regulation by synaptic activity. Brain Res Mol Brain Res 38:179–190 Meffert MK, Baltimore D (2005) Physiological functions for brain NF-kappaB. Trends Neurosci 28:37–43 Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D (2003) NF-kappa B functions in synaptic signaling and behavior. Nat Neurosci 6:1072–1078 Miterski B, Bohringer S, Klein W, Sindern E, Haupts M et al (2002) Inhibitors in the NFkappaB cascade comprise prime candidate genes predisposing to multiple sclerosis, especially in selected combinations. Genes Immun 3:211–219 Moerman AM, Mao X, Lucas MM, Barger SW (1999) Characterization of a neuronal kappaB- binding factor distinct from NF-kappaB. Brain Res Mol Brain Res 67:303–315 . NF-κB in Brain Diseases 305 6 Role of NF-κB in Brain Diseases Because NF-κB plays many important roles, it is not surprising that dysregulation of NF-κB signaling is involved in the pathogenesis. arthritis, in ammatory bowel diseases, bone resorption, and some neurodegenerative diseases reviewed by (Kumar et al., 2004). Investigation of the roles of NF-κB in brain diseases is just beginning,. staining indicates an increase of p65 level i n the axons first and, subsequently, in neuronal cell bodies. The increased p65 level also occurs in the neighboring microglia and astrocytes. This increase