Sustained, neuron-specific IKK/NF-κB activation generates a selective neuroinflammatory response promoting local neurodegeneration with aging

Molecular Neurodegeneration

Bernd Baumann¹  Thomas Wirth¹  Michael Lattke¹  Ayesha Maqbool¹ 

[1] Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, Ulm 89081 Germany

关键词: Dentate gyrus;    Spatial learning and memory;    Bdnf;    IKK2;    NF-κB;    Neurodegeneration;    Neuroinflammation;   

Others  :  862123
DOI  :  10.1186/1750-1326-8-40

 received in 2013-04-25, accepted in 2013-10-09,  发布年份 2013

【 摘 要 】

Background

Increasing evidence indicates that neuroinflammation is a critical factor contributing to the progression of various neurodegenerative diseases. The IKK/NF-κB signalling system is a central regulator of inflammation, but it also affects neuronal survival and differentiation. A complex interplay between different CNS resident cells and infiltrating immune cells, which produce and respond to various inflammatory mediators, determines whether neuroinflammation is beneficial or detrimental. The IKK/NF-κB system is involved in both production of and responses to these mediators, although the precise contribution depends on the cell type as well as the cellular context, and is only partially understood. Here we investigated the specific contribution of neuronal IKK/NF-κB signalling on the regulation of neuroinflammatory processes and its consequences. To address this issue, we established and analysed a conditional gain-of-function mouse model that expresses a constitutively active allele of IKK2 in principal forebrain neurons (IKK2^nCA). Proinflammatory gene and growth factor expression, histopathology, microgliosis, astrogliosis, immune cell infiltration and spatial learning were assessed at different timepoints after persistent canonical IKK2/NF-κB activation.

Results

In contrast to other cell types and organ systems, chronic IKK2/NF-κB signalling in forebrain neurons of adult IKK2^nCA animals did not cause a full-blown inflammatory response including infiltration of immune cells. Instead, we found a selective inflammatory response in the dentate gyrus characterized by astrogliosis, microgliosis and Tnf-α upregulation. Furthermore, downregulation of the neurotrophic factor Bdnf correlated with a selective and progressive atrophy of the dentate gyrus and a decline in hippocampus-dependent spatial learning. Neuronal degeneration was associated with increased Fluoro-jade staining, but lacked activation of apoptosis. Remarkably, neuronal loss could be partially reversed when chronic IKK2/NF-κB signalling was turned off and Bdnf expression was restored.

Conclusion

Our results demonstrate that persistent IKK2/NF-κB signalling in forebrain neurons does not induce overall neuroinflammation, but elicits a selective inflammatory response in the dentate gyrus accompanied by decreased neuronal survival and impaired learning and memory. Our findings further suggest that chronic activation of neuronal IKK2/NF-κB signalling, possibly as a consequence of neuroinflammatory conditions, is able to induce apoptosis-independent neurodegeneration via paracrine suppression of Bdnf synthesis.

【 授权许可】

   
2013 Maqbool et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH: Mechanisms underlying inflammation in neurodegeneration. Cell 2010, 140:918-934.
• [2]Mattson MP, Meffert MK: Roles for NF-kappaB in nerve cell survival, plasticity, and disease. Cell Death Differ 2006, 13:852-860.
• [3]Ghosh S, Hayden MS: New regulators of NF-kappaB in inflammation. Nat Rev Immunol 2008, 8:837-848.
• [4]Hayden MS, Ghosh S: Shared principles in NF-kappaB signaling. Cell 2008, 132:344-362.
• [5]Perkins ND: Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol 2007, 8:49-62.
• [6]Kaltschmidt B, Kaltschmidt C: NF-kappaB in the nervous system. Cold Spring Harb Perspect Biol 2009, 1:a001271.
• [7]Kaltschmidt B, Widera D, Kaltschmidt C: Signaling via NF-kappaB in the nervous system. Biochim Biophys Acta 2005, 1745:287-299.
• [8]Memet S: NF-kappaB functions in the nervous system: from development to disease. Biochem Pharmacol 2006, 72:1180-1195.
• [9]Herrmann O, Baumann B, de Lorenzi R, Muhammad S, Zhang W, Kleesiek J, Malfertheiner M, Kohrmann M, Potrovita I, Maegele I, et al.: IKK mediates ischemia-induced neuronal death. Nat Med 2005, 11:1322-1329.
• [10]Khoshnan A, Ko J, Tescu S, Brundin P, Patterson PH: IKKalpha and IKKbeta regulation of DNA damage-induced cleavage of huntingtin. PLoS One 2009, 4:e5768.
• [11]Lattke M, Magnutzki A, Walther P, Wirth T, Baumann B: Nuclear factor kappab activation impairs ependymal ciliogenesis and links neuroinflammation to hydrocephalus formation. J Neurosci 2012, 32:11511-11523.
• [12]Mattson MP, Camandola S: NF-kappaB in neuronal plasticity and neurodegenerative disorders. J Clin Invest 2001, 107:247-254.
• [13]Nurmi A, Lindsberg PJ, Koistinaho M, Zhang W, Juettler E, Karjalainen-Lindsberg ML, Weih F, Frank N, Schwaninger M, Koistinaho J: Nuclear factor-kappaB contributes to infarction after permanent focal ischemia. Stroke 2004, 35:987-991.
• [14]Song XQ, Lv LX, Li WQ, Hao YH, Zhao JP: The interaction of nuclear factor-kappa B and cytokines is associated with schizophrenia. Biol Psychiatr 2009, 65:481-488.
• [15]Thompson LM, Aiken CT, Kaltenbach LS, Agrawal N, Illes K, Khoshnan A, Martinez-Vincente M, Arrasate M, O’Rourke JG, Khashwji H, et al.: IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. J Cell Biol 2009, 187:1083-1099.
• [16]Harari OA, Liao JK: NF-kappaB and innate immunity in ischemic stroke. Ann N Y Acad Sci 2010, 1207:32-40.
• [17]Ridder DA, Schwaninger M: NF-kappaB signaling in cerebral ischemia. Neuroscience 2009, 158:995-1006.
• [18]Baumann B, Wagner M, Aleksic T, von Wichert G, Weber CK, Adler G, Wirth T: Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo. J Clin Invest 2007, 117:1502-1513.
• [19]Maier HJ, Schips TG, Wietelmann A, Kruger M, Brunner C, Sauter M, Klingel K, Bottger T, Braun T, Wirth T: Cardiomyocyte-specific IkappaB kinase (IKK)/NF-kappaB activation induces reversible inflammatory cardiomyopathy and heart failure. Proc Natl Acad Sci U S A 2012, 109:11794-11799.
• [20]Sunami Y, Leithauser F, Gul S, Fiedler K, Guldiken N, Espenlaub S, Holzmann KH, Hipp N, Sindrilaru A, Luedde T, et al.: Hepatic activation of IKK/NFkappaB signaling induces liver fibrosis via macrophage-mediated chronic inflammation. Hepatology 2012, 56:1117-1128.
• [21]Mayford M, Bach ME, Huang YY, Wang L, Hawkins RD, Kandel ER: Control of memory formation through regulated expression of a CaMKII transgene. Science 1996, 274:1678-1683.
• [22]Gupta SC, Sundaram C, Reuter S, Aggarwal BB: Inhibiting NF-kappaB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta 2010, 1799:775-787.
• [23]Oeckl P, Lattke M, Wirth T, Baumann B, Ferger B: Astrocyte-specific IKK2 activation in mice is sufficient to induce neuroinflammation but does not increase susceptibility to MPTP. Neurobiol Dis 2012, 48(3):481-487. doi: 10.1016/j.nbd.2012.06.010. Epub 2012 Jun 30
• [24]Hagihara H, Toyama K, Yamasaki N, Miyakawa T: Dissection of hippocampal dentate gyrus from adult mouse. J Vis Exp 2009, 33:e1543. doi:10.3791/1543
• [25]Gutierrez H, Hale VA, Dolcet X, Davies A: NF-kappaB signalling regulates the growth of neural processes in the developing PNS and CNS. Development 2005, 132:1713-1726.
• [26]Schmeisser MJ, Baumann B, Johannsen S, Vindedal GF, Jensen V, Hvalby OC, Sprengel R, Seither J, Maqbool A, Magnutzki A, et al.: IkappaB kinase/nuclear factor kappaB-dependent insulin-like growth factor 2 (Igf2) expression regulates synapse formation and spine maturation via Igf2 receptor signaling. J Neurosci 2012, 32:5688-5703.
• [27]Ahn HJ, Hernandez CM, Levenson JM, Lubin FD, Liou HC, Sweatt JD: c-Rel, an NF-kappaB family transcription factor, is required for hippocampal long-term synaptic plasticity and memory formation. Learn Mem 2008, 15:539-549.
• [28]Imielski Y, Schwamborn JC, Luningschror P, Heimann P, Holzberg M, Werner H, Leske O, Puschel AW, Memet S, Heumann R, et al.: Regrowing the adult brain: NF-kappaB controls functional circuit formation and tissue homeostasis in the dentate gyrus. PLoS One 2012, 7:e30838.
• [29]Kaltschmidt B, Ndiaye D, Korte M, Pothion S, Arbibe L, Prullage M, Pfeiffer J, Lindecke A, Staiger V, Israel A, et al.: NF-kappaB regulates spatial memory formation and synaptic plasticity through protein kinase A/CREB signaling. Mol Cell Biol 2006, 26:2936-2946.
• [30]Kassed CA, Willing AE, Garbuzova-Davis S, Sanberg PR, Pennypacker KR: Lack of NF-kappaB p50 exacerbates degeneration of hippocampal neurons after chemical exposure and impairs learning. Exp Neurol 2002, 176:277-288.
• [31]Meffert MK, Baltimore D: Physiological functions for brain NF-kappaB. Trends Neurosci 2005, 28:37-43.
• [32]Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D: NF-kappa B functions in synaptic signaling and behavior. Nat Neurosci 2003, 6:1072-1078.
• [33]Merlo E, Freudenthal R, Romano A: The IkappaB kinase inhibitor sulfasalazine impairs long-term memory in the crab Chasmagnathus. Neuroscience 2002, 112:161-172.
• [34]Vorhees CV, Williams MT: Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 2006, 1:848-858.
• [35]Ascano M, Bodmer D, Kuruvilla R: Endocytic trafficking of neurotrophins in neural development. Trends Cell Biol 2012, 22:266-273.
• [36]Chen DY, Stern SA, Garcia-Osta A, Saunier-Rebori B, Pollonini G, Bambah-Mukku D, Blitzer RD, Alberini CM: A critical role for IGF-II in memory consolidation and enhancement. Nature 2011, 469:491-497.
• [37]Huang YZ, Mei L: [Neuregulin/ErbB signal transduction pathway in the development of nervous system]. Sheng Li Ke Xue Jin Zhan 2001, 32:197-203.
• [38]Caldeira MV, Melo CV, Pereira DB, Carvalho R, Correia SS, Backos DS, Carvalho AL, Esteban JA, Duarte CB: Brain-derived neurotrophic factor regulates the expression and synaptic delivery of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunits in hippocampal neurons. J Biol Chem 2007, 282:12619-12628.
• [39]Slipczuk L, Bekinschtein P, Katche C, Cammarota M, Izquierdo I, Medina JH: BDNF activates mTOR to regulate GluR1 expression required for memory formation. PLoS One 2009, 4:e6007.
• [40]Song I, Huganir RL: Regulation of AMPA receptors during synaptic plasticity. Trends Neurosci 2002, 25:578-588.
• [41]Cunha C, Brambilla R, Thomas KL: A simple role for BDNF in learning and memory? Front Mol Neurosci 2010, 3:1.
• [42]Sheikh AM, Malik M, Wen G, Chauhan A, Chauhan V, Gong CX, Liu F, Brown WT, Li X: BDNF-Akt-Bcl2 antiapoptotic signaling pathway is compromised in the brain of autistic subjects. J Neurosci Res 2010, 88:2641-2647.
• [43]Camandola S, Mattson MP: NF-kappa B as a therapeutic target in neurodegenerative diseases. Expert Opin Ther Targets 2007, 11:123-132.
• [44]van Loo G, De Lorenzi R, Schmidt H, Huth M, Mildner A, Schmidt-Supprian M, Lassmann H, Prinz MR, Pasparakis M: Inhibition of transcription factor NF-kappaB in the central nervous system ameliorates autoimmune encephalomyelitis in mice. Nat Immunol 2006, 7:954-961.
• [45]Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, Cai D: Hypothalamic programming of systemic ageing involving IKK-beta, NF-kappaB and GnRH. Nature 2013, 497:211-216.
• [46]Mattson MP, Culmsee C, Yu Z, Camandola S: Roles of nuclear factor kappaB in neuronal survival and plasticity. J Neurochem 2000, 74:443-456.
• [47]Boersma MC, Dresselhaus EC, De Biase LM, Mihalas AB, Bergles DE, Meffert MK: A requirement for nuclear factor-kappaB in developmental and plasticity-associated synaptogenesis. J Neurosci 2011, 31:5414-5425.
• [48]Christoffel DJ, Golden SA, Dumitriu D, Robison AJ, Janssen WG, Ahn HF, Krishnan V, Reyes CM, Han MH, Ables JL, et al.: IkappaB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J Neurosci 2011, 31:314-321.
• [49]Gutierrez H, Davies AM: Regulation of neural process growth, elaboration and structural plasticity by NF-kappaB. Trends Neurosci 2011, 34:316-325.
• [50]Russo SJ, Wilkinson MB, Mazei-Robison MS, Dietz DM, Maze I, Krishnan V, Renthal W, Graham A, Birnbaum SG, Green TA, et al.: Nuclear factor kappa B signaling regulates neuronal morphology and cocaine reward. J Neurosci 2009, 29:3529-3537.
• [51]Kaltschmidt C, Kaltschmidt B, Baeuerle PA: Stimulation of ionotropic glutamate receptors activates transcription factor NF-kappa B in primary neurons. Proc Natl Acad Sci U S A 1995, 92:9618-9622.
• [52]Grilli M, Goffi F, Memo M, Spano P: 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 1996, 271:15002-15007.
• [53]Grilli M, Pizzi M, Memo M, Spano P: Neuroprotection by aspirin and sodium salicylate through blockade of NF-kappaB activation. Science 1996, 274:1383-1385.
• [54]Sarnico I, Boroni F, Benarese M, Alghisi M, Valerio A, Battistin L, Spano P, Pizzi M: Targeting IKK2 by pharmacological inhibitor AS602868 prevents excitotoxic injury to neurons and oligodendrocytes. J Neural Transm 2008, 115:693-701.
• [55]Deng W, Aimone JB, Gage FH: New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci 2010, 11:339-350.
• [56]Denis-Donini S, Dellarole A, Crociara P, Francese MT, Bortolotto V, Quadrato G, Canonico PL, Orsetti M, Ghi P, Memo M, et al.: Impaired adult neurogenesis associated with short-term memory defects in NF-kappaB p50-deficient mice. J Neurosci 2008, 28:3911-3919.
• [57]Sarnico I, Lanzillotta A, Boroni F, Benarese M, Alghisi M, Schwaninger M, Inta I, Battistin L, Spano P, Pizzi M: NF-kappaB p50/RelA and c-Rel-containing dimers: opposite regulators of neuron vulnerability to ischaemia. J Neurochem 2009, 108:475-485.
• [58]Lee RM, Gillet G, Burnside J, Thomas SJ, Neiman P: Role of Nr13 in regulation of programmed cell death in the bursa of Fabricius. Genes Dev 1999, 13:718-728.
• [59]Ricca A, Biroccio A, Trisciuoglio D, Cippitelli M, Zupi G, Del Bufalo D: relA over-expression reduces tumorigenicity and activates apoptosis in human cancer cells. Br J Canc 2001, 85:1914-1921.
• [60]Lu B, Pang PT, Woo NH: The yin and yang of neurotrophin action. Nat Rev Neurosci 2005, 6:603-614.
• [61]Yamada K, Nabeshima T: Brain-derived neurotrophic factor/TrkB signaling in memory processes. J Pharmacol Sci 2003, 91:267-270.
• [62]Xiu MH, Hui L, Dang YF, Hou TD, Zhang CX, Zheng YL, Chen da C, Kosten TR, Zhang XY: Decreased serum BDNF levels in chronic institutionalized schizophrenia on long-term treatment with typical and atypical antipsychotics. Prog Neuropsychopharmacol Biol Psychiatr 2009, 33:1508-1512.
• [63]Zuccato C, Cattaneo E: Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol 2009, 5:311-322.
• [64]Block ML, Zecca L, Hong JS: Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 2007, 8:57-69.
• [65]Sofroniew MV, Vinters HV: Astrocytes: biology and pathology. Acta Neuropathol 2010, 119:7-35.
• [66]Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW: From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008, 9:46-56.
• [67]Saha RN, Liu X, Pahan K: Up-regulation of BDNF in astrocytes by TNF-alpha: a case for the neuroprotective role of cytokine. J Neuroimmune Pharmacol 2006, 1:212-222.
• [68]Boycott HE, Wilkinson JA, Boyle JP, Pearson HA, Peers C: Differential involvement of TNF alpha in hypoxic suppression of astrocyte glutamate transporters. Glia 2008, 56:998-1004.
• [69]Campbell KJ, Rocha S, Perkins ND: Active repression of antiapoptotic gene expression by RelA(p65) NF-kappa B. Mol Cell 2004, 13:853-865.
• [70]Dallas M, Boycott HE, Atkinson L, Miller A, Boyle JP, Pearson HA, Peers C: Hypoxia suppresses glutamate transport in astrocytes. J Neurosci 2007, 27:3946-3955.
• [71]Fuchikami M, Yamamoto S, Morinobu S, Takei S, Yamawaki S: Epigenetic regulation of BDNF gene in response to stress. Psychiatr Investig 2010, 7:251-256.
• [72]Li X, Wei W, Ratnu VS, Bredy TW: On the potential role of active DNA demethylation in establishing epigenetic states associated with neural plasticity and memory. Neurobiol Learn Mem 2013, 105:125-132.
• [73]Lubin FD, Roth TL, Sweatt JD: Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J Neurosci 2008, 28:10576-10586.
• [74]Sik A, Hajos N, Gulacsi A, Mody I, Freund TF: The absence of a major Ca2+ signaling pathway in GABAergic neurons of the hippocampus. Proc Natl Acad Sci U S A 1998, 95:3245-3250.
• [75]Han HJ, Allen CC, Buchovecky CM, Yetman MJ, Born HA, Marin MA, Rodgers SP, Song BJ, Lu HC, Justice MJ, et al.: Strain background influences neurotoxicity and behavioral abnormalities in mice expressing the tetracycline transactivator. J Neurosci 2012, 32:10574-10586.
• [76]Schips TG, Wietelmann A, Hohn K, Schimanski S, Walther P, Braun T, Wirth T, Maier HJ: FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model. Cardiovasc Res 2010, 91:587-597.
• [77]Schmidt-Strassburger U, Schips TG, Maier HJ, Kloiber K, Mannella F, Braunstein KE, Holzmann K, Ushmorov A, Liebau S, Boeckers TM, Wirth T: Expression of constitutively active FoxO3 in murine forebrain leads to a loss of neural progenitors. FASEB J 2012, 26(12):4990-5001. doi: 10.1096/fj.12-208587. Epub 2012 Aug 30.
• [78]Schmued LC, Albertson C, Slikker W Jr: Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration. Brain Res 1997, 751:37-46.
• [79]Paxinos G, Franklin KBJ: The Mouse Brain in Stereotaxic Coordinates. 2001.