Neurochemical Research

, Volume 44, Issue 1, pp 49–60 | Cite as

TNFα and IL-1β but not IL-18 Suppresses Hippocampal Long-Term Potentiation Directly at the Synapse

  • G. Aleph PrietoEmail author
  • Liqi Tong
  • Erica D. Smith
  • Carl W. Cotman
Original Paper


CNS inflammatory responses are linked to cognitive impairment in humans. Research in animal models supports this connection by showing that inflammatory cytokines suppress long-term potentiation (LTP), the best-known cellular correlate of memory. Cytokine-induced modulation of LTP has been previously studied in vivo or in brain slices, two experimental approaches containing multiple cell populations responsive to cytokines. In their target cells, cytokines commonly increase the expression of multiple cytokines, thus increasing the complexity of brain cytokine networks even after single-cytokine challenges. Whether cytokines suppress LTP by direct effects on neurons or by indirect mechanisms is still an open question. Here, we evaluated the effect of a major set of inflammatory cytokines including tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β) and interleukin-18 (IL-18) on chemically-induced LTP (cLTP) in isolated hippocampal synaptosomes of mice, using fluorescence analysis of single-synapse long-term potentiation (FASS-LTP). We found that TNFα and IL-1β suppress synaptosomal cLTP. In contrast, cLTP was not affected by IL-18, at a concentration previously shown to block LTP in hippocampal slices. We also found that IL-18 does not impair cLTP or brain-derived neurotrophic factor (BDNF) signaling in primary hippocampal neuronal cultures. Thus, using both synaptosomes and neuron cultures, our data suggest that IL-18 impairs LTP by indirect mechanisms, which may depend on non-neuronal cells, such as glia. Notably, our results demonstrate that TNFα and IL-1β directly suppress hippocampal plasticity via neuron-specific mechanisms. A better understanding of the brain’s cytokine networks and their final molecular effectors is crucial to identify specific targets for intervention.


Inflammation Cytokines Hippocampus Synaptosomes cLTP FASS-LTP 



Work in the authors’ lab is supported by National Institutes of Health Grants R21-AG048506, P01-AG000538 and RO1-AG34667 (to C. W. C.), as well as by UC MEXUS-CONACYT Grant CN-16-170 (to G. A. P. and C. W. C.).

Compliance with Ethical Standards

Conflict of interest

The authors declare no competing financial interest.


  1. 1.
    Prieto-Moreno GA, Rosenstein Y (2006) The links between the neuroendocrine and the immune systems: views of an immunologist. In: Joseph-Bravo P (ed) Molecular endocrinology, 1 edn. Research Signpost, Kerala, pp 171–192Google Scholar
  2. 2.
    Yirmiya R, Goshen I (2011) Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 25:181–213Google Scholar
  3. 3.
    Griffin WS (2013) Neuroinflammatory cytokine signaling and Alzheimer’s disease. N Engl J Med 368:770–771Google Scholar
  4. 4.
    Heppner FL, Ransohoff RM, Becher B (2015) Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16:358–372Google Scholar
  5. 5.
    Becher B, Spath S, Goverman J (2017) Cytokine networks in neuroinflammation. Nat Rev Immunol 17:49–59Google Scholar
  6. 6.
    Prieto GA, Cotman CW (2017) Cytokines and cytokine networks target neurons to modulate long-term potentiation. Cytokine Growth Factor Rev 34:27–33Google Scholar
  7. 7.
    Andreasson KI, Bachstetter AD, Colonna M, Ginhoux F, Holmes C, Lamb B, Landreth G, Lee DC, Low D, Lynch MA, Monsonego A, O’Banion MK, Pekny M, Puschmann T, Russek-Blum N, Sandusky LA, Selenica ML, Takata K, Teeling J, Town T, Van Eldik LJ (2016) Targeting innate immunity for neurodegenerative disorders of the central nervous system. J Neurochem 138:653–693Google Scholar
  8. 8.
    Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14:388–405Google Scholar
  9. 9.
    Vitkovic L, Konsman JP, Bockaert J, Dantzer R, Homburger V, Jacque C (2000) Cytokine signals propagate through the brain. Mol Psychiatry 5:604–615Google Scholar
  10. 10.
    Brosseron F, Krauthausen M, Kummer M, Heneka MT (2014) Body fluid cytokine levels in mild cognitive impairment and Alzheimer’s disease: a comparative overview. Mol Neurobiol 50:534–544Google Scholar
  11. 11.
    Lai KSP, Liu CS, Rau A, Lanctot KL, Kohler CA, Pakosh M, Carvalho AF, Herrmann N (2017) Peripheral inflammatory markers in Alzheimer’s disease: a systematic review and meta-analysis of 175 studies. J Neurol Neurosurg Psychiatry. Google Scholar
  12. 12.
    Swardfager W, Lanctot K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010) A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry 68:930–941Google Scholar
  13. 13.
    Barrientos RM, Hein AM, Frank MG, Watkins LR, Maier SF (2012) Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats. J Neurosci 32:14641–14648Google Scholar
  14. 14.
    Cibelli M, Fidalgo AR, Terrando N, Ma D, Monaco C, Feldmann M, Takata M, Lever IJ, Nanchahal J, Fanselow MS, Maze M (2010) Role of interleukin-1beta in postoperative cognitive dysfunction. Ann Neurol 68:360–368Google Scholar
  15. 15.
    Frank MG, Barrientos RM, Hein AM, Biedenkapp JC, Watkins LR, Maier SF (2010) IL-1RA blocks E. coli-induced suppression of Arc and long-term memory in aged F344 × BN F1 rats. Brain Behav Immun 24:254–262Google Scholar
  16. 16.
    Hein AM, Stasko MR, Matousek SB, Scott-McKean JJ, Maier SF, Olschowka JA, Costa AC, O’Banion MK (2010) Sustained hippocampal IL-1beta overexpression impairs contextual and spatial memory in transgenic mice. Brain Behav Immun 24:243–253Google Scholar
  17. 17.
    Trompet S, de Craen AJ, Slagboom P, Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Ford I, Gaw A, Macfarlane PW, Packard CJ, Stott DJ, Jukema JW, Westendorp RG (2008) Genetic variation in the interleukin-1 beta-converting enzyme associates with cognitive function. The PROSPER study. Brain 131:1069–1077Google Scholar
  18. 18.
    Zhu W, Cao FS, Feng J, Chen HW, Wan JR, Lu Q, Wang J (2017) NLRP3 inflammasome activation contributes to long-term behavioral alterations in mice injected with lipopolysaccharide. Neuroscience 343:77–84Google Scholar
  19. 19.
    Bossu P, Ciaramella A, Salani F, Bizzoni F, Varsi E, Di Iulio F, Giubilei F, Gianni W, Trequattrini A, Moro ML, Bernardini S, Caltagirone C, Spalletta G (2008) Interleukin-18 produced by peripheral blood cells is increased in Alzheimer’s disease and correlates with cognitive impairment. Brain Behav Immun 22:487–492Google Scholar
  20. 20.
    Ohgidani M, Kato TA, Sagata N, Hayakawa K, Shimokawa N, Sato-Kasai M, Kanba S (2016) TNF-alpha from hippocampal microglia induces working memory deficits by acute stress in mice. Brain Behav Immun 55:17–24Google Scholar
  21. 21.
    Sahin TD, Karson A, Balci F, Yazir Y, Bayramgurler D, Utkan T (2015) TNF-alpha inhibition prevents cognitive decline and maintains hippocampal BDNF levels in the unpredictable chronic mild stress rat model of depression. Behav Brain Res 292:233–240Google Scholar
  22. 22.
    Terrando N, Monaco C, Ma D, Foxwell BM, Feldmann M, Maze M (2010) Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci USA 107:20518–20522Google Scholar
  23. 23.
    Shi JQ, Wang BR, Jiang WW, Chen J, Zhu YW, Zhong LL, Zhang YD, Xu J (2011) Cognitive improvement with intrathecal administration of infliximab in a woman with Alzheimer’s disease. J Am Geriatr Soc 59:1142–1144Google Scholar
  24. 24.
    Tobinick EL, Gross H (2008) Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflamm 5:2Google Scholar
  25. 25.
    McKim DB, Niraula A, Tarr AJ, Wohleb ES, Sheridan JF, Godbout JP (2016) Neuroinflammatory dynamics underlie memory impairments after repeated social defeat. J Neurosci 36:2590–2604Google Scholar
  26. 26.
    Alvarez-Arellano L, Pedraza-Escalona M, Blanco-Ayala T, Camacho-Concha N, Cortes-Mendoza J, Perez-Martinez L, Pedraza-Alva G (2018) Autophagy impairment by caspase-1-dependent inflammation mediates memory loss in response to beta-amyloid peptide accumulation. J Neurosci Res 96:234–236Google Scholar
  27. 27.
    Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791Google Scholar
  28. 28.
    Paula-Lima AC, Brito-Moreira J, Ferreira ST (2013) Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer’s disease. J Neurochem 126:191–202Google Scholar
  29. 29.
    Nicholson DA, Yoshida R, Berry RW, Gallagher M, Geinisman Y (2004) Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments. J Neurosci 24:7648–7653Google Scholar
  30. 30.
    Morrison JH, Baxter MG (2012) The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat Rev Neurosci 13:240–250Google Scholar
  31. 31.
    Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39Google Scholar
  32. 32.
    Murray CA, Lynch MA (1998) Evidence that increased hippocampal expression of the cytokine interleukin-1 beta is a common trigger for age- and stress-induced impairments in long-term potentiation. J Neurosci 18:2974–2981Google Scholar
  33. 33.
    Vereker E, O’Donnell E, Lynch MA (2000) The inhibitory effect of interleukin-1beta on long-term potentiation is coupled with increased activity of stress-activated protein kinases. J Neurosci 20:6811–6819Google Scholar
  34. 34.
    Tong L, Prieto GA, Kramar EA, Smith ED, Cribbs DH, Lynch G, Cotman CW (2012) Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1beta via p38 mitogen-activated protein kinase. J Neurosci 32:17714–17724Google Scholar
  35. 35.
    Chapman TR, Barrientos RM, Ahrendsen JT, Maier SF, Patterson SL (2010) Synaptic correlates of increased cognitive vulnerability with aging: peripheral immune challenge and aging interact to disrupt theta-burst late-phase long-term potentiation in hippocampal area CA1. J Neurosci 30:7598–7603Google Scholar
  36. 36.
    Cunningham AJ, Murray CA, O’Neill LA, Lynch MA, O’Connor JJ (1996) Interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro. Neurosci Lett 203:17–20Google Scholar
  37. 37.
    Bellinger FP, Madamba S, Siggins GR (1993) Interleukin 1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus. Brain Res 628:227–234Google Scholar
  38. 38.
    Hoshino K, Hasegawa K, Kamiya H, Morimoto Y (2017) Synapse-specific effects of IL-1beta on long-term potentiation in the mouse hippocampus. Biomed Res 38:183–188Google Scholar
  39. 39.
    Cumiskey D, Curran BP, Herron CE, O’Connor JJ (2007) A role for inflammatory mediators in the IL-18 mediated attenuation of LTP in the rat dentate gyrus. Neuropharmacology 52:1616–1623Google Scholar
  40. 40.
    Cumiskey D, Pickering M, O’Connor JJ (2007) Interleukin-18 mediated inhibition of LTP in the rat dentate gyrus is attenuated in the presence of mGluR antagonists. Neurosci Lett 412:206–210Google Scholar
  41. 41.
    Curran B, O’Connor JJ (2001) The pro-inflammatory cytokine interleukin-18 impairs long-term potentiation and NMDA receptor-mediated transmission in the rat hippocampus in vitro. Neuroscience 108:83–90Google Scholar
  42. 42.
    Butler MP, O’Connor JJ, Moynagh PN (2004) Dissection of tumor-necrosis factor-alpha inhibition of long-term potentiation (LTP) reveals a p38 mitogen-activated protein kinase-dependent mechanism which maps to early-but not late-phase LTP. Neuroscience 124:319–326Google Scholar
  43. 43.
    Tancredi V, D’Arcangelo G, Grassi F, Tarroni P, Palmieri G, Santoni A, Eusebi F (1992) Tumor necrosis factor alters synaptic transmission in rat hippocampal slices. Neurosci Lett 146:176–178Google Scholar
  44. 44.
    Prieto GA, Snighda S, Baglietto-Vargas D, Smith ED, Berchtold N, Tong L, Ajami D, LaFerla FM, Rebek J, Cotman CW (2015) Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1b in the aged hippocampus. Proc Natl Acad Sci USA 112:E5078-5087Google Scholar
  45. 45.
    Whittaker VP (1993) Thirty years of synaptosome research. J Neurocytol 22:735–742Google Scholar
  46. 46.
    Wilhelm BG, Mandad S, Truckenbrodt S, Krohnert K, Schafer C, Rammner B, Koo SJ, Classen GA, Krauss M, Haucke V, Urlaub H, Rizzoli SO (2014) Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science 344:1023–1028Google Scholar
  47. 47.
    Sandoval ME, Horch P, Cotman CW (1978) Evaluation of glutamate as a hippocampal neurotransmitter: glutamate uptake and release from synaptosomes. Brain Res 142:285–299Google Scholar
  48. 48.
    Daniel JA, Malladi CS, Kettle E, McCluskey A, Robinson PJ (2012) Analysis of synaptic vesicle endocytosis in synaptosomes by high-content screening. Nat Protoc 7:1439–1455Google Scholar
  49. 49.
    Michaelis EK, Michaelis ML, Chang HH, Kitos TE (1983) High affinity Ca2+-stimulated Mg2+-dependent ATPase in rat brain synaptosomes, synaptic membranes, and microsomes. J Biol Chem 258:6101–6108Google Scholar
  50. 50.
    Michaelis ML, Michaelis EK, Myers SL (1979) Adenosine modulation of synaptosomal dopamine release. Life Sci 24:2083–2092Google Scholar
  51. 51.
    Prieto GA, Trieu BH, Dang CT, Bilousova T, Gylys KH, Berchtold NC, Lynch G, Cotman CW (2017) Pharmacological rescue of long-term potentiation in Alzheimer diseased synapses. J Neurosci 37:1197–1212Google Scholar
  52. 52.
    Lu W, Man H, Ju W, Trimble WS, MacDonald JF, Wang YT (2001) Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron 29:243–254Google Scholar
  53. 53.
    Musleh W, Bi X, Tocco G, Yaghoubi S, Baudry M (1997) Glycine-induced long-term potentiation is associated with structural and functional modifications of alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid receptors. Proc Natl Acad Sci USA 94:9451–9456Google Scholar
  54. 54.
    Kramar EA, Lin B, Lin CY, Arai AC, Gall CM, Lynch G (2004) A novel mechanism for the facilitation of theta-induced long-term potentiation by brain-derived neurotrophic factor. J Neurosci 24:5151–5161Google Scholar
  55. 55.
    Chen TJ, Wang DC, Chen SS (2009) Amyloid-beta interrupts the PI3K-Akt-mTOR signaling pathway that could be involved in brain-derived neurotrophic factor-induced Arc expression in rat cortical neurons. J Neurosci Res 87:2297–2307Google Scholar
  56. 56.
    Rex CS, Lin CY, Kramar EA, Chen LY, Gall CM, Lynch G (2007) Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci 27:3017–3029Google Scholar
  57. 57.
    Smith ED, Prieto GA, Tong L, Sears-Kraxberger I, Rice JD, Steward O, Cotman CW (2014) Rapamycin and interleukin-1beta impair brain-derived neurotrophic factor-dependent neuron survival by modulating autophagy. J Biol Chem 289:20615–20629Google Scholar
  58. 58.
    Fortin DA, Davare MA, Srivastava T, Brady JD, Nygaard S, Derkach VA, Soderling TR (2010) Long-term potentiation-dependent spine enlargement requires synaptic Ca2+-permeable AMPA receptors recruited by CaM-kinase I. J Neurosci 30:11565–11575Google Scholar
  59. 59.
    Park M, Salgado JM, Ostroff L, Helton TD, Robinson CG, Harris KM, Ehlers MD (2006) Plasticity-induced growth of dendritic spines by exocytic trafficking from recycling endosomes. Neuron 52:817–830Google Scholar
  60. 60.
    Chen RQ, Wang SH, Yao W, Wang JJ, Ji F, Yan JZ, Ren SQ, Chen Z, Liu SY, Lu W (2011) Role of glycine receptors in glycine-induced LTD in hippocampal CA1 pyramidal neurons. Neuropsychopharmacology 36:1948–1958Google Scholar
  61. 61.
    Baumgarth N, Roederer M (2000) A practical approach to multicolor flow cytometry for immunophenotyping. J Immunol Methods 243:77–97Google Scholar
  62. 62.
    Hulspas R, O’Gorman MR, Wood BL, Gratama JW, Sutherland DR (2009) Considerations for the control of background fluorescence in clinical flow cytometry. Cytometry Part B 76:355–364Google Scholar
  63. 63.
    Menon V, Thomas R, Ghale AR, Reinhard C, Pruszak J (2014) Flow cytometry protocols for surface and intracellular antigen analyses of neural cell types. J Vis Exp 94:52241Google Scholar
  64. 64.
    Cotman CW, Haycock JW, White WF (1976) Stimulus-secretion coupling processes in brain: analysis of noradrenaline and gamma-aminobutyric acid release. J Physiol 254:475–505Google Scholar
  65. 65.
    Michaelis ML, Jiang L, Michaelis EK (2017) Isolation of synaptosomes, synaptic plasma membranes, and synaptic junctional complexes. Methods Mol Biol 1538:107–119Google Scholar
  66. 66.
    Snigdha S, Prieto GA, Petrosyan A, Loertscher BM, Dieskau AP, Overman LE, Cotman CW (2016) H3K9me3 Inhibition improves memory, promotes spine formation, and increases BDNF levels in the aged hippocampus. J Neurosci 36:3611–3622Google Scholar
  67. 67.
    Carlos AJ, Tong L, Prieto GA, Cotman CW (2017) IL-1beta impairs retrograde flow of BDNF signaling by attenuating endosome trafficking. J Neuroinflamm 14:29Google Scholar
  68. 68.
    Fu Y, Huang ZJ (2010) Differential dynamics and activity-dependent regulation of alpha- and beta-neurexins at developing GABAergic synapses. Proc Natl Acad Sci USA 107:22699–22704Google Scholar
  69. 69.
    Mondin M, Labrousse V, Hosy E, Heine M, Tessier B, Levet F, Poujol C, Blanchet C, Choquet D, Thoumine O (2011) Neurexin-neuroligin adhesions capture surface-diffusing AMPA receptors through PSD-95 scaffolds. J Neurosci 31:13500–13515Google Scholar
  70. 70.
    Prieto GA, Cotman CW (2017) On the road towards the global analysis of human synapses. Neural Regen Res 12:1586–1589Google Scholar
  71. 71.
    Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440:1054–1059Google Scholar
  72. 72.
    Manabe T, Renner P, Nicoll RA (1992) Postsynaptic contribution to long-term potentiation revealed by the analysis of miniature synaptic currents. Nature 355:50–55Google Scholar
  73. 73.
    Park M, Penick EC, Edwards JG, Kauer JA, Ehlers MD (2004) Recycling endosomes supply AMPA receptors for LTP. Science 305:1972–1975Google Scholar
  74. 74.
    Man HY, Wang Q, Lu WY, Ju W, Ahmadian G, Liu L, D’Souza S, Wong TP, Taghibiglou C, Lu J, Becker LE, Pei L, Liu F, Wymann MP, MacDonald JF, Wang YT (2003) Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons. Neuron 38:611–624Google Scholar
  75. 75.
    Sui L, Wang J, Li BM (2008) Role of the phosphoinositide 3-kinase-Akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex. Learn Mem 15:762–776Google Scholar
  76. 76.
    Hu H, Qin Y, Bochorishvili G, Zhu Y, van Aelst L, Zhu JJ (2008) Ras signaling mechanisms underlying impaired GluR1-dependent plasticity associated with fragile X syndrome. J Neurosci 28:7847–7862Google Scholar
  77. 77.
    Pen Y, Borovok N, Reichenstein M, Sheinin A, Michaelevski I (2016) Membrane-tethered AKT kinase regulates basal synaptic transmission and early phase LTP expression by modulation of post-synaptic AMPA receptor level. Hippocampus 26:1149–1167Google Scholar
  78. 78.
    Tong L, Balazs R, Soiampornkul R, Thangnipon W, Cotman CW (2008) Interleukin-1 beta impairs brain derived neurotrophic factor-induced signal transduction. Neurobiol Aging 29:1380–1393Google Scholar
  79. 79.
    Alboni S, Montanari C, Benatti C, Sanchez-Alavez M, Rigillo G, Blom JM, Brunello N, Conti B, Pariante MC, Tascedda F (2014) Interleukin 18 activates MAPKs and STAT3 but not NF-kappaB in hippocampal HT-22 cells. Brain Behav Immun 40:85–94Google Scholar
  80. 80.
    Zhou J, Ping FF, Lv WT, Feng JY, Shang J (2014) Interleukin-18 directly protects cortical neurons by activating PI3K/AKT/NF-kappaB/CREB pathways. Cytokine 69:29–38Google Scholar
  81. 81.
    Pfau ML, Menard C, Russo SJ (2017) Inflammatory mediators in mood disorders: therapeutic opportunities. Annu Rev Pharmacol Toxicol. Google Scholar
  82. 82.
    Erion JR, Wosiski-Kuhn M, Dey A, Hao S, Davis CL, Pollock NK, Stranahan AM (2014) Obesity elicits interleukin 1-mediated deficits in hippocampal synaptic plasticity. J Neurosci 34:2618–2631Google Scholar
  83. 83.
    Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P (1995) Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett 202:17–20Google Scholar
  84. 84.
    Tarkowski E, Blennow K, Wallin A, Tarkowski A (1999) Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin Immunol 19:223–230Google Scholar
  85. 85.
    Gale SC, Gao L, Mikacenic C, Coyle SM, Rafaels N, Murray Dudenkov T, Madenspacher JH, Draper DW, Ge W, Aloor JJ, Azzam KM, Lai L, Blackshear PJ, Calvano SE, Barnes KC, Lowry SF, Corbett S, Wurfel MM, Fessler MB (2014) APOepsilon4 is associated with enhanced in vivo innate immune responses in human subjects. J Allergy Clin Immunol 134:127–134Google Scholar
  86. 86.
    Vitek MP, Brown CM, Colton CA (2009) APOE genotype-specific differences in the innate immune response. Neurobiol Aging 30:1350–1360Google Scholar
  87. 87.
    Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C, Alzheimer’s Disease Neuroimaging I, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM (2017) ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549:523–527Google Scholar
  88. 88.
    Dinarello CA (2011) Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 117:3720–3732Google Scholar
  89. 89.
    Friedman WJ (2001) Cytokines regulate expression of the type 1 interleukin-1 receptor in rat hippocampal neurons and glia. Exp Neurol 168:23–31Google Scholar
  90. 90.
    Farrar WL, Kilian PL, Ruff MR, Hill JM, Pert CB (1987) Visualization and characterization of interleukin 1 receptors in brain. J Immunol 139:459–463Google Scholar
  91. 91.
    Smith DE, Lipsky BP, Russell C, Ketchem RR, Kirchner J, Hensley K, Huang Y, Friedman WJ, Boissonneault V, Plante MM, Rivest S, Sims JE (2009) A central nervous system-restricted isoform of the interleukin-1 receptor accessory protein modulates neuronal responses to interleukin-1. Immunity 30:817–831Google Scholar
  92. 92.
    Neumann H, Schweigreiter R, Yamashita T, Rosenkranz K, Wekerle H, Barde YA (2002) Tumor necrosis factor inhibits neurite outgrowth and branching of hippocampal neurons by a rho-dependent mechanism. J Neurosci 22:854–862Google Scholar
  93. 93.
    Zhu CB, Lindler KM, Owens AW, Daws LC, Blakely RD, Hewlett WA (2010) Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology 35:2510–2520Google Scholar
  94. 94.
    Murray CA, McGahon B, McBennett S, Lynch MA (1997) Interleukin-1 beta inhibits glutamate release in hippocampus of young, but not aged, rats. Neurobiol Aging 18:343–348Google Scholar
  95. 95.
    Zhu CB, Blakely RD, Hewlett WA (2006) The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology 31:2121–2131Google Scholar
  96. 96.
    Gardoni F, Boraso M, Zianni E, Corsini E, Galli CL, Cattabeni F, Marinovich M, Di Luca M, Viviani B (2011) Distribution of interleukin-1 receptor complex at the synaptic membrane driven by interleukin-1beta and NMDA stimulation. J Neuroinflamm 8:14Google Scholar
  97. 97.
    Cheng X, Yang L, He P, Li R, Shen Y (2010) Differential activation of tumor necrosis factor receptors distinguishes between brains from Alzheimer’s disease and non-demented patients. J Alzheimers Dis 19:621–630Google Scholar
  98. 98.
    Iosif RE, Ekdahl CT, Ahlenius H, Pronk CJ, Bonde S, Kokaia Z, Jacobsen SE, Lindvall O (2006) Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis. J Neurosci 26:9703–9712Google Scholar
  99. 99.
    Naude PJ, Dobos N, van der Meer D, Mulder C, Pawironadi KG, den Boer JA, van der Zee EA, Luiten PG, Eisel UL (2014) Analysis of cognition, motor performance and anxiety in young and aged tumor necrosis factor alpha receptor 1 and 2 deficient mice. Behav Brain Res 258:43–51Google Scholar
  100. 100.
    Saresella M, La Rosa F, Piancone F, Zoppis M, Marventano I, Calabrese E, Rainone V, Nemni R, Mancuso R, Clerici M (2016) The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease. Mol Neurodegener 11:23Google Scholar
  101. 101.
    Singhal G, Jaehne EJ, Corrigan F, Toben C, Baune BT (2014) Inflammasomes in neuroinflammation and changes in brain function: a focused review. Front Neurosci 8:315Google Scholar
  102. 102.
    Youm YH, Grant RW, McCabe LR, Albarado DC, Nguyen KY, Ravussin A, Pistell P, Newman S, Carter R, Laque A, Munzberg H, Rosen CJ, Ingram DK, Salbaum JM, Dixit VD (2013) Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab 18:519–532Google Scholar
  103. 103.
    Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493:674–678Google Scholar
  104. 104.
    Felderhoff-Mueser U, Schmidt OI, Oberholzer A, Buhrer C, Stahel PF (2005) IL-18: a key player in neuroinflammation and neurodegeneration? Trends Neurosci 28:487–493Google Scholar
  105. 105.
    Wheeler RD, Brough D, Le Feuvre RA, Takeda K, Iwakura Y, Luheshi GN, Rothwell NJ (2003) Interleukin-18 induces expression and release of cytokines from murine glial cells: interactions with interleukin-1 beta. J Neurochem 85:1412–1420Google Scholar
  106. 106.
    Guillot-Sestier MV, Town T (2013) Innate immunity in Alzheimer’s disease: a complex affair. CNS Neurol Disord Drug Targets 12:593–607Google Scholar
  107. 107.
    Montgomery SL, Mastrangelo MA, Habib D, Narrow WC, Knowlden SA, Wright TW, Bowers WJ (2011) Ablation of TNF-RI/RII expression in Alzheimer’s disease mice leads to an unexpected enhancement of pathology: implications for chronic pan-TNF-alpha suppressive therapeutic strategies in the brain. Am J Pathol 179:2053–2070Google Scholar
  108. 108.
    Donzis EJ, Tronson NC (2014) Modulation of learning and memory by cytokines: signaling mechanisms and long term consequences. Neurobiol Learn Mem 115:68–77Google Scholar
  109. 109.
    Maher FO, Clarke RM, Kelly A, Nally RE, Lynch MA (2006) Interaction between interferon gamma and insulin-like growth factor-1 in hippocampus impacts on the ability of rats to sustain long-term potentiation. J Neurochem 96:1560–1571Google Scholar
  110. 110.
    Kelly RJ, Minogue AM, Lyons A, Jones RS, Browne TC, Costello DA, Denieffe S, O’Sullivan C, Connor TJ, Lynch MA (2013) Glial activation in AbetaPP/PS1 mice is associated with infiltration of IFNgamma-producing cells. J Alzheimers Dis 37:63–75Google Scholar
  111. 111.
    Kitazawa M, Cheng D, Tsukamoto MR, Koike MA, Wes PD, Vasilevko V, Cribbs DH, LaFerla FM (2011) Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal beta-catenin pathway function in an Alzheimer’s disease model. J Immunol 187:6539–6549Google Scholar
  112. 112.
    Chang R, Yee KL, Sumbria RK (2017) Tumor necrosis factor alpha inhibition for Alzheimer’s disease. J Cent Nerv Syst Dis 9:1179573517709278Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute for Memory Impairments and Neurological DisordersUniversity of CaliforniaIrvineUSA

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