The Impact of an Imbalance Between Proinflammatory and Anti-inflammatory Influences on Synaptic function in the Aged Brain

  • Marina Lynch

There is now a significant body of evidence indicating that, with age, the brain is exposed to a number of stresses. One of these is a decrease in the concentration of antiinflammatory cytokines that exert significant neuroprotective effects. On the basis of recent findings, it seems reasonable to propose that among the most critical neuroprotective effects of IL-4 and IL-10 is maintenance of microglia in a quiescent state, preventing excessive release of proinflammatory cytokines like IL-1μ, which have been shown to negative impact on hippocampal plasticity. It must therefore be concluded that it is an imbalance between proinflammatory and anti-inflammatory cytokines that leads to age-related deficits in synaptic function and that strategies that restore the balance are likely to be beneficial in reducing the deterioration of function that accompanies age.


Proinflammatory Cytokine Microglial Activation Free Radical Theory Eicosapentanoic Acid Hippocampal Concentration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

10. References

  1. Ali, M., 2005, The oxidative-dysoxygenative model of ageing. J. Integr. Med. 7: 1.Google Scholar
  2. Aloisi, F., 2001, Immune function of microglia. Glia 36: 165.PubMedGoogle Scholar
  3. Aloisi, F., Ria, F., Penna, G. and Adorini, L., 1998, Microglia are more efficient than astrocytes in antigen processing and in Th1 but not Th2 cell activation. J. Immunol. 160: 4671.PubMedGoogle Scholar
  4. Amano, Y., Lee, S.W. and Allison, A.C., 1993, Inhibition by glucocorticoids of the formation of interleukin-1α, interleukin-1β, and interleukin-6: mediation by decreased mRNA stability. Mol. Pharmacol. 43: 176.PubMedGoogle Scholar
  5. Avital, A., Goshen, I., Kamsler, A., Segal, M., Iverfeldt, K., Richter-Levin, G. and Yitmiya, R., 2003, Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity. Hippocampus 13: 826.PubMedGoogle Scholar
  6. Balschun, D., Wetzel, W., Del Rey, A., Pitossi, F., Schneider, H., Zuschratter, W. and Besedovsky, H.O., 2004, Interleukin-6: a cytokine to forget. FASEB J. 18: 1788.PubMedGoogle Scholar
  7. Barnes, C.A., 1988, Spatial learning and memory processes: the search for their neurobiological mechanisms in the rat. Trends Neurosci. 11: 163.PubMedGoogle Scholar
  8. Barry, C.E., Nolan, Y., Clarke, R.M., Lynch, A. and Lynch, M.A., 2005, Activation of c-Jun-N-terminal kinase is critical in mediating lipopolysaccharide-induced changes in rat hippocampus. J. Neurochem. 93: 221.PubMedGoogle Scholar
  9. Belardelli, F., 1995, Role of interferons and other cytokines in the regulation of the immune response. Acta Pathol. Microbiol. Immunol. Scand. 103: 161.Google Scholar
  10. Block, M.L. and Hong, J.S., 2005, Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog. Neurobiol. 76: 77.PubMedGoogle Scholar
  11. Bluthe, R.M., Castanon, N., Pousset, F., Bristow, A., Ball, C., Lestage, J., Michaud, B., Kelley, K.W., Dantzer, R., 1999, Central injection of IL-10 antagonizes the behavioural effects of lipopolysaccharide in rats. Psychoneuroendocrinol. 24: 301.Google Scholar
  12. Bodles, A.M. and Barger, S.W., 2004, Cytokines and the aging brain-what we don’t know might help us. Trends Neurosci. 27: 621.PubMedGoogle Scholar
  13. Boehm, U., Klamp, T., Groot, M. and Howard, J.C., 1997, Cellular responses to interferon-γ. Ann. Rev. Immunol. 15: 749.Google Scholar
  14. Bonhaus, D.W., Perry, W.B. and McNamara, J.O., 1990, Decreased density. But not number, of N-methyl-D-aspartate, glycine and phencyclidine binding sites in the hippocampus of senescent rats. Brain Res. 532: 82.PubMedGoogle Scholar
  15. Borrego, F., Alonso, M.C., Galiani, M.D., Carracedo, J., Ramirez, R., Ostos, B., Pena, J. and Solana, R., 1999, NK phenotype markers and IL-2 response in NK cells from elderly people. Exp. Gerontol. 34: 253.PubMedGoogle Scholar
  16. Brodie, C., Goldreich, N., Haiman, T. and Kazimirsky, G., 1998, Functional IL-4 receptors on mouse astrocytes: IL-4 inhibits astrocyte activation and induces NGF secretion. J. Neuroimmunol. 81: 20.PubMedGoogle Scholar
  17. Cantorna, M., Woodward, W., Hayes, C.E. and DeLuca, H.F., 1998, 1, 25-Dihydroxyvitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-β1 and IL-4. J. Immunol. 160: 5314.Google Scholar
  18. Castella, M.A., Meda, L., Gasperini, S., Calzetti, F. and Bonora, S., 1994, Interleukin-10 up regulates IL-1 receptor antagonist production from lipopolysaccharide-stimulated human polymorphonuclear leukocytes by delaying mRNA degradation. J. Exp. Med. 179: 1695.Google Scholar
  19. Clarke, R.M. and Lynch, M.A., 2005, Atorvastatin modulates the lipopolysaccharide-induced impairment in long-term potentiation in the rat hippocampus. Soc. Neurosci. Abstr. 792:1.Google Scholar
  20. Costelloe, C.E., Lyons, A. and Lynch, M.A., 2005, Minocycline attenuates the inhibition of LTP induced by amyloid-β. Soc. Neurosci. Abstr. 910:9.Google Scholar
  21. Curran, B. and O’Connor, J.J., 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.PubMedGoogle Scholar
  22. Curran, B.P., Murray, H.J. and O’Connor, J.J., 2003, A role for c-Jun N-terminal kinase in the inhibition of long-term potentiation by interleukin-1beta and long-term depression in the rat dentate gyrus in vitro. Neuroscience 118: 347.PubMedGoogle Scholar
  23. Davies, C.A., Loddickm, S.A., Toulmondm, S., Stroemerm, R.P., Hunt, J. and Rothwell, N.J., 1999, The progression and topographic distribution of interleukin-1beta expression after permanent middle cerebral artery occlusion in the rat. J. Cereb. Blood Flow Metab. 19: 87.PubMedGoogle Scholar
  24. De la Asuncion, J.G., Millan, A., Pla, R., Bruseghini, L., Esteras, A., Pallardo, F.V., Saster, J. and Vina, J., 1996. Mitochondrial glutathione oxidation correlates with age-associated oxidative damage to mitochondrial DNA. FASEB J. 10: 333.PubMedGoogle Scholar
  25. Delgado, M., 2003, Inhibition of interferon (IFN) γ-induced Jak-STAT1 activation in microglia by vasoactive intestinal peptide. J. Biol. Chem. 278: 27620.PubMedGoogle Scholar
  26. DeLuca, H.F. and Cantorna, M.T., 2001, Vitamin D: its role and uses in immunology. FASEB J. 15: 2579.PubMedGoogle Scholar
  27. Effros, R.B., 2005, Roy Walford and the immunologic theory of ageing. Immunity Ageing 2: 7.PubMedGoogle Scholar
  28. Fabris, N., 1992, Biomarkers of ageing in the neuroendocrine-immune domain. Time for a new theory of ageing? Ann. N.Y. Acad. Sci. 663: 335.PubMedGoogle Scholar
  29. Felzien, L.K., McDonald, J.T., Gleason, S.M., Berman, N.E. and Klein, R.M., 2001, Increased chemokine gene expression during aging in the murine brain. Brain Res. 26: 137.Google Scholar
  30. Fickenscher, H., Hor, S., Kupers, H., Knappe, A., Wittman, A. and Sticht, H., 2002, The interleukin-10 family of cytokines. Trends Immunol. 23: 89.PubMedGoogle Scholar
  31. Finbloom, D.S. and Winestock, K.D., 1995, IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 and STAT3 complexes in human T cells and monocytes. J. Immunol. 155: 1079.PubMedGoogle Scholar
  32. Forster, M.J., Dubey, A., Dawson, K.M., Stutts, W.A., Lal, H. and Sohal, R.S., 1996, Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. Proc. Nat. Acad. Sci. USA 93: 4765.PubMedGoogle Scholar
  33. Gabbita, S.P., Butterfield, D.A., Hensley, K., Shaw, W. and Carney, J.M., 1997, Aging and caloric restriction affect mitochondrial respiration and lipid membrane status: an electron paramagnetic resonance investigation. Free Rad. Biol. Med. 23: 191.PubMedGoogle Scholar
  34. Gajewski, T.F. and Fitch, F.W., 1988, Anti-proliferative effect of IFN-γ in immune regulation. I. IFN-γ inhibits the proliferation of Th2 but not Th1 murine helper lymphocyte clones. J. Immunol. 140: 4245.PubMedGoogle Scholar
  35. Geng, Y., Gulbins, E., Altman, A. and Lotz, M., 1994, Monocyte deactivation by interleukin-10 via inhibition of tyrosine kinase activity and the Ras signaling pathway. Proc. Nat. Acad. Sci. USA 91: 8602.PubMedGoogle Scholar
  36. Giulian, D. and Baker, T., 1986, Characterisation of Ameboid microglia isolated from developing mammalian brain. J. Neurosci. 6: 2163.PubMedGoogle Scholar
  37. Giusto, N.M., Roque, M.E. and Ilincheta de Boschero, M.E., 1992, Effects of aging on the content, composition and synthesis of sphingomyelin in the central nervous system. Lipids 27: 835.PubMedGoogle Scholar
  38. Godbout, J.P. and Johnson, R.W., 2004, Interleukin-6 in the aging brain. J. Immunol. 147: 141.Google Scholar
  39. Gottfries, C.G., 1990, Neurochemical aspects on aging and diseases with cognitive impairment. J. Neurosci. Res. 27: 541.PubMedGoogle Scholar
  40. Grilli, M., Barbieri, I., Basudev, H., Brusa, R., Casati, C., Lozza, G. and Ongini, E., 2000, Interleukin-10 modulates neuronal threshold of vulnerability to ischaemic damage. Eur. J. Neurosci. 12: 2265.PubMedGoogle Scholar
  41. Gu, Z., Wortwein, G., Yu, J. and Perez-Polo, J.R., 2000, Model for aging in the basal forebrain cholinergic system. Antioxid. Redox Signal 2: 437.PubMedGoogle Scholar
  42. Haddad, J.J., Saade, N.E. and Safieh-Garabedian, B., 2003, Interleukin-10 and the regulation of mitogen-activated protein kinases: are these signaling modules targets for anti-inflammatory action of this cytokine? Cell Signal 15: 255.PubMedGoogle Scholar
  43. Hanisch, U.K., 2002, Microglia as a source and target of cytokines. Glia 40: 140.PubMedGoogle Scholar
  44. Haque, S.J., Wu, Q., Kammer, W., Friedrich, K., Smith, J.M., Kerr, I.M., Stark, G.R. and Williams, B.R., 1997, Receptor-associated constitutive protein tyrosine phosphatase activity controls the kinase function of JAK1. Proc. Natl. Acad. Sci. USA 94: 8563.PubMedGoogle Scholar
  45. Harman, D., 2003, The free radical theory of aging. Antioxid. Redox Signal 5: 557.PubMedGoogle Scholar
  46. Hasan, M. and Glees, P., 1973, Ultrastructural age changes in hippocampal neurons, synapses and neuroglia. Exp. Gerontol. 8: 75.PubMedGoogle Scholar
  47. Hauss-Wegrzyniak, B., Vraniak, P. and Wenk, G.L., 1999, The effects of a novel NSAID on chronic neuro-inflammation are age dependent. Neurobiol. Aging 20: 305.PubMedGoogle Scholar
  48. Hauss-Wegrzyniak, B., Lynch, M.A., Vraniak, P.D. and Wenk, G.L., 2002, Chronic brain inflammation results in cell loss in the entorhinal cortex and impaired LTP in perforant path-granule cell synapses. Exp. Neurol. 176: 336.PubMedGoogle Scholar
  49. Horvath, C.M. and Darnell, J.E., 1997, The state of Stats: recent developments in the study of signal transduction to the nucleus. Curr. Opin. Cell Biol. 9: 233.PubMedGoogle Scholar
  50. Iglesias, B.M., Cerase, J., Ceracchini, C., Levi, G. and Aloisi, F., 1997, Analysis of B7-1 and B7-2 costimulatory ligands in cultured mouse microglia: upregulation by interferon-γ and lipopolysaccharide and downregulation by interleukin-10, prostaglandin E2 and cyclic AMP-elevating agents. J. Neuroimmunol. 72: 83.Google Scholar
  51. Ingram, D.K., Garafalo, P., Spangler, E.L., Mantione, C.R., Odano, I. and London, E.D., 1992, Reduced density of NMDA receptors and increased sensitivity to dizocipline-induced learning impairment in aged rats. Brain Res. 580: 273.PubMedGoogle Scholar
  52. Ke, Z. and Gibson, G.E., 2004, Selective response of various brain cell types during neurodegeneration induced by mild impairment of oxidative metabolism. Neurochem. Int. 45: 361.PubMedGoogle Scholar
  53. Kelly, A., Lynch, A., Vereker, E., Nolan, Y., Quennan, P., Whittaker, E., O’Neill, L. and Lynch, M.A., 2001, The anti-inflammatory cytokine, interleukin (IL)-10, blocks the inhibitory effect of IL-1β on long-term potentiation. J. Biol. Chem. 276: 45564.PubMedGoogle Scholar
  54. Kelly, A., Vereker, E., Brady, M., Barry, C., Loscher, C., Mills, K.H.G. and Lynch, M.A., 2003, Activation of p38 plays a pivotal role in the inhibitory effect of lipopolysaccharide and interleukin-1β-induced inhibition of long-term potentiation in rat dentate gyrus. J. Biol. Chem. 278: 19453.PubMedGoogle Scholar
  55. Kern, J.A., Lamb, R.J., Reed, J.C., Daniele, R.P. and Nowell, P.C., 1988, Dexamethasone inhibition of interleukin 1 beta production by human monocytes. J. Clin. Invest. 81: 237.PubMedGoogle Scholar
  56. Kim, E., Lee, J., Namkoong, S., Um, S. and Park, J., 2002, Interferon regulatory factor-1 mediates interferon-γ-induced apoptosis in ovarian carcinoma cells. J. Cell Biochem. 85: 369.PubMedGoogle Scholar
  57. Kim, H., Whang, S., Woo, M., Park, J., Kim, W. and Han, I., 2004, Sodium butyrate suppresses interferon-gamma-, but not lipopolysaccharide-mediated induction of nitric oxide and tumor necrosis factor-alpha in microglia. J. Neuroimmunol. 151: 85.PubMedGoogle Scholar
  58. Knudsen, P.J., Dinarello, C.A. and Strom, T.B., 1987, Glucocorticoids inhibit transcriptional and post-transcriptional expression of Interleukin 1 in U937 cells. J. Immunol. 2139: 4129.Google Scholar
  59. Kontoyiannis, D., Kotlyarov, A., Carballo, E., Alexopoulou, L., Blackshear, P.J., Gaestel, M., Davis, R., Flavell, R. and Kollias, G., 2001, Intereukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology. EMBO J. 20: 3760.PubMedGoogle Scholar
  60. Kreutsberg, G.W., 1996, Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19: 312.Google Scholar
  61. Kullberg, S., Aldskogius, H. and Ulfhake, B., 2001, Microglial activation, emergence of ED1-expressing cells and clusterin upregulation in the aging rat CNS, with special reference to the spinal cord. Brain Res. 899: 169.PubMedGoogle Scholar
  62. Land, W.G., 2004, Ageing and immunosuppression in kidney transplantation. Exp. Clin. Transplant. 2: 229.PubMedGoogle Scholar
  63. Ledeboer, A., Breve, J.J., Poole, S., Tilders, F.J. and Van Dam, A.M., 2000, Interleukin-10, interleukin-4, and transforming growth factor-beta differentially regulate lipopolysaccharide-induced production of pro-inflammatory cytokines and nitric oxide in co-cultures of rat astroglial and microglial cells. Glia 30:134.PubMedGoogle Scholar
  64. Ledeboer, A., Breve, J.J.P., Wierinckx, A., van der Jagt, S., Bristow, A.F., Leysen, J.E., Tilders, F.J.H. and Van Dam A.-M., 2002, Expression and regulation of interleukin-10 and interleukin-10 receptor in rat astroglial and microglial cells. Eur. J. Neurosci. 16: 1175.PubMedGoogle Scholar
  65. Leonard, W.J. and O’Shea, J.J., 1998, Jaks and Stats: biological Implications. Ann. Rev. Immunol. 16: 293.Google Scholar
  66. Li, A.J., Katafuchi, T., Oda, S., Hori, T. and Oomura, Y., 1997, Interleukin-6 inhibits long-term potentiation in rat hippocampal slices. Brain Res. 748: 30.PubMedGoogle Scholar
  67. Li, Y., Liu, L., Barger, S.W. and Griffin, W.S., 2003, Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J. Neurosci. 23: 1605.PubMedGoogle Scholar
  68. Lindberg, C., Selenica, M.L., Westlind-Danielsson, A. and Schultzberg, M., 2005, Beta-amyloid protein structure determines the nature of cytokine release from rat microglia. J. Mol. Neurosci. 27: 1.PubMedGoogle Scholar
  69. Loane, D.J., Lynch, A.M., Minogue, A.M., Kilroy, D., Woods, O. and Lynch, M.A., 2005, Eicosapentaenoic acid reduces the age-related increase in microglial activation in the adult hippocampus. Soc. Neurosci. Abstr. 910: 5.Google Scholar
  70. Lonergan, P.E., Martin, D.S.D., Horrobin, D.F. and Lynch, M.A., 2002, Neuroprotective effect of eicosapentanoic acid in hippocampus of rats exposed to γ-irradiation. J. Biol. Chem. 277: 20804.PubMedGoogle Scholar
  71. Lonergan, P.E., Martin, D.S.D., Horrobin, D.F. and Lynch, M.A., 2004, Neuroprotective actions of eicosapentanoic acid on lipopolysaccharide-induced dysfunction in rat hippocampus. J. Neurochem. 91: 20.PubMedGoogle Scholar
  72. Lynch, M.A., 2004, Long-term potentiation and memory. Physiol. Rev. 84: 87.PubMedGoogle Scholar
  73. Lynch, A.M. and Lynch, M.A., 2001, The age-related increase in IL-1 type I receptor in rat hippocampus is coupled with an increase in caspase-3 activation. Eur. J. Neurosci. 15: 1779.Google Scholar
  74. Lynch, A., Moore, M., Craig, S., Lonergan, P., Martin, D. and Lynch, M.A., 2003, Analysis of interleukin-1β-induced cell signaling activation in rat hippocampus following exposure to gamma irradiation. J. Biol. Chem. 278: 51075.PubMedGoogle Scholar
  75. Lynch, A., Walsh, C., Delaney, A., Nolan, Y., Campbell, V. and Lynch, M.A., 2004, Lipopolysaccharide-induced increase in signaling in hippocampus is abrogated by IL-10 - a role for IL-1β? J. Neurochem. 88: 635.PubMedGoogle Scholar
  76. Lynch, A.M., Loane, D.J., Minogue, A.M. and Lynch, M.A., 2005, Cytokine modulation by eicosapentaenoic acid in the aged hippocampus Soc. Neurosci. Abstr. 910: 4.Google Scholar
  77. Maher, F.O., Nolan, Y. and Lynch, M.A., 2005, Downregulation of IL-4-induced signaling in hippocampus contributes to deficits in LTP in the aged rat. Neurobiol. Aging 26: 717.PubMedGoogle Scholar
  78. Martin, D.S., Lonergan, P.E., Boland, B., Fogarty, M.P., Brady, M., Horrobin, D.F., Campbell, V.A. and Lynch, M.A., 2002, Apoptotic changes in the aged brain are triggered by interleukin-1beta-induced activation of p38 and reversed by treatment with eicosapentanoic acid. J. Biol. Chem. 277: 34239.PubMedGoogle Scholar
  79. McGahon, B.M., Martin, D.S.D., Horrobin, D.F. and Lynch, M.A., 1999 Age-related changes in synaptic function: analysis of the effect of dietary supplementation with ω-3 fatty acids. Neurosci. 94: 305.Google Scholar
  80. McGeer, P.L. and McGeer, E.G., 2004, Inflammation and neurodegeneration in Parkinson's disease. Parkinson Relat. Disord., Suppl. 1: S3.Google Scholar
  81. Mesples, B., Plaisant, F. and Gressens, P., 2003, Effects of interleukin-10 on neonatal excitotoxic brain lesions in mice. Dev. Brain Res. 141: 25.Google Scholar
  82. Minogue, A.M., Schmid, A.W., Fogarty, M.P., Moore, A.C., Campbell, V.A., Herron, C.E. and Lynch, M.A., 2003, Activation of the c-Jun N-terminal kinase signaling cascade mediates the effect of amyloid-β on long term potentiation and cell death in hippocampus. J. Biol. Chem. 278: 27971.PubMedGoogle Scholar
  83. Mizuno, T., Sawada, M., Marunounchi, T. and Suzumura, A., 1994, Production of interleukin-10 by mouse glial cells in culture. Biochem. Biophys. Res. Commun. 205: 1907.PubMedGoogle Scholar
  84. Mocchetti, I. and Wrathall, J.R., 1995, Neurotrophic factors in central nervous system trauma. J. Neurotrauma 12: 853.PubMedGoogle Scholar
  85. Molina-Holgado, E., Vela, J.M., Arevalo-Martin, A. and Guaza, C., 2001, LPS/IFN-gamma cytotoxicity in oligodendroglial cells: role of nitric oxide and protection by the anti-inflammatory cytokine IL-10. Eur. J. Neurosci. 13: 493.PubMedGoogle Scholar
  86. Molina-Holgado, E., Arevalo-Martin, A., Ortiz, S., Vela, J.M. and Guaza, C., 2002, Theiler’s virus infection induces the expression of cyclooxygenase-2 in murine astrocytes: inhibition by the anti-inflammatory cytokines interleukin-4 and interleukin-10. Neurosci. Lett. 324: 237.PubMedGoogle Scholar
  87. Moore, M. and Lynch, M.A., 2004, Does treatment with dexamethasone prevent age-related changes in hippocampus. Soc. Neurosci. Abstr. 565: 14.Google Scholar
  88. Moore, K.W., Malefyt, R., Coffman, R.L. and O’Garra, A., 2001, Interleukin-10 and the interleukin-10 receptor. Ann. Rev. Immunol. 19: 683.Google Scholar
  89. Moore, M.E., Piazza, A., McCartney, Y. and Lynch, M.A., 2005, Evidence that vitamin D(3) reverses age-related inflammatory changes in the rat hippocampus. Biochem. Soc. Trans. 33: 573.PubMedGoogle Scholar
  90. Murray, C.A. and Lynch, M.A., 1998a, Dietary supplementation with vitamin E reverses the age-related deficit in long-term potentiation in dentate gyrus. J. Biol. Chem. 273: 12161.PubMedGoogle Scholar
  91. Murray, C. and Lynch, M.A., 1998b, Evidence that increased hippocampal expression of the cytokine, IL-1β, is a common trigger for age and stress-induced impairments in long-term potentiation. J. Neurosci. 18: 2974.PubMedGoogle Scholar
  92. Nally, R., Walsh, M., Nolan, Y. and Lynch, M.A., 2004, Age-related changes in the rat hippocampus and the effect of exogenously administered interleukin-1β. Soc. Neurosci. Abstr. 565: 2.Google Scholar
  93. Nelms, K., Keegan, A.D., Zamorano, J., Ryan, J.J. and Paul, W.E., 1999, The IL-4 receptor: signaling mechanisms and biologic functions. Ann. Rev. Immunol. 17: 701.Google Scholar
  94. Neumann, H., Boucraut, J., Hahnel, C., Misgeld, T. and Wekerle, H., 1996, Neuronal control of MHC class II inducibility in rat astrocytes and microglia. Eur. J. Neurosci. 8: 2582.PubMedGoogle Scholar
  95. Nguyen, V.T. and Benveniste, E.N., 2000, Involvement of STAT-1 and its family members in interferon-gamma induction of CD40 transcription in microglia/macrophages. J. Biol. Chem. 275: 23674.PubMedGoogle Scholar
  96. Nolan, Y., Maher, F.O., Martin, D.S., Clarke, R.M., Brady, M.T., Bolton, A.E., Mills, K.H. and Lynch, M.A., 2005, Role of interleukin-4 in regulation of age-related inflammatory changes in the hippocampus. J. Biol. Chem. 280: 9354.PubMedGoogle Scholar
  97. Ogura, K., Ogawa, M., Yoshida, M., 1994, Effects of ageing on microglia in the normal rat brain: immunohistochemical observation. Neuroreport 5: 1224.PubMedGoogle Scholar
  98. O’Keefe, G.M., Nguyen, V.T., Benveniste, E.N., 2002 Regulation and function of class II major histocompatibility complex, CD40, and B7 expression in macrophages and microglia: Implications in neurological diseases. J. Neurovirol. 8: 496.PubMedGoogle Scholar
  99. O’Shea, J.J., 1997, Jaks, Stats, cytokine signal transduction and immunoregulation: are we there yet? Immunity 7: 1.PubMedGoogle Scholar
  100. Park, J., Kim, I., Oh, Y.J., Lee, K., Han, P.L. and Choi, E.J., 1997, Activation of c-Jun N-terminal kinase antagonises an anti-apoptotic action of Bcl-2. J. Biol. Chem. 272: 16725.PubMedGoogle Scholar
  101. Pellmar, T.C., Hollinden, G.E. and Sarvey, J.M., 1991, Free radicals accelerate the decay of long-term potentiation in field CA1 of guinea-pig hippocampus, Neuroscience 44: 353.PubMedGoogle Scholar
  102. Pestka, S., Krause, C.D., Sarkar, D., Walter, M.R., Shi, Y. and Fisher, P.B., 2004, Interleukin-10 and related cytokines and receptors. Ann. Rev. Immunol. 22: 929.Google Scholar
  103. Roth, G.S. and Joseph, J.A., 1994, Cellular and molecular mechanisms of impaired dopaminergic function during aging. Ann. N.Y. Acad. Sci. 719: 129.PubMedGoogle Scholar
  104. Rozovsky, I., Finch, C.E. and Morgan, T.E., 1998, Age-related activation of microglia and astrocytes: in vitro studies show persistent phenotypes of aging, increase proliferation and resistance to down-regulation. Neurobiol. Aging 19: 97.PubMedGoogle Scholar
  105. Sawada, M., Suzumura, A., Hosoya, H., Marunouchi, T. and Nagatsu, T., 1999, Interleukin-10 inhibits both production of cytokines and expression of cytokine receptors in microglia. J. Neurochem. 72: 1466.PubMedGoogle Scholar
  106. Schipper, H.M., 2004, Brain iron deposition and the free radical-mitochondrial theory of aging. Age Res. Rev. 3: 265.Google Scholar
  107. Schneider, H., Pitossi, F., Balschun, D., Wagner, A., Del Rey, A. and Besedovsky, H.O., 1998, A neuromodulatory role of interleukin-1beta in the hippocampus. Proc. Natl. Acad. Sci. USA 95: 7778.PubMedGoogle Scholar
  108. Shigenaga, M.K., Hagen, T.M. and Ames, B.N., 1994, Oxidative damage and mitochondrial decay in aging. Proc. Natl. Acad. Sci. USA 91: 10771.PubMedGoogle Scholar
  109. Sims, J.E., 2002, IL-1 and IL-18 receptors, and their extended family. Curr. Opin. Immunol. 14: 117.PubMedGoogle Scholar
  110. Sloane, J.A., Hollander, W., Moss, M.B., Rosene, D.L. and Abraham, C.R., 1999, Increased microglial activation and protein nitration in white matter of the aging monkey. Neurobiol. Aging 20: 395.PubMedGoogle Scholar
  111. Slotkin, T.A., Cousins, M.M., Tate, C.A. and Seidler, F.J., 2005, Serotonergic cell signaling in an animal model of aging and depression: olfactory bulbectomy elicits different adaptations in brain regions of young adult vs aging rats. Neuropsychopharmacology 30: 52.PubMedGoogle Scholar
  112. Smith, P., Dunne D.W. and Fallon, P.G., 2001, Defective in vivo induction of functional type 2 cytokine responses in aged mice. Eur. J. Immunol. 31: 1495.PubMedGoogle Scholar
  113. Stirling, D.P., Koochesfahani, K.M., Steeves, J.D. and Tetzlaff, W., 2005, Minocycline as a neuroprotective agent. Neuroscientist 11: 308.PubMedGoogle Scholar
  114. Strehlow, I. and Schindler, C., 1998, Amino-terminal signal transducer and activators of transcription (STAT) domains regulate nuclear translocation and Stat deactivation. J. Biol. Chem. 273: 28049.PubMedGoogle Scholar
  115. Streit, W.J., 2000, Microglial response to brain injury: a brief synopsis. Toxicol. Pathol. 28: 28.PubMedGoogle Scholar
  116. Szczepanik, A.M. and Ringheim, G.E., 2003, IL-10 and glucocorticoids inhibit Abeta(1-42)- and lipopolysaccharide-induced pro-inflammatory cytokine and chemokine induction in the central nervous system. J. Alzheimers Dis. 5: 105.PubMedGoogle Scholar
  117. Szczepanik, A.M., Funes, S., Petko, W. and Ringheim, G.E., 2001, IL-4, IL-10 and IL-13 modulate A beta(1-42)-induced cytokine and chemokine production in primary murine microglia and a human monocyte cell line. J. Neuroimmunol. 113: 49.PubMedGoogle Scholar
  118. Tan, J., Town, T., Crawford, F., Mori, T., DelleDonne, A., Crescentini, R., Obregon, D., Flavell, R.A. and Mullan, M.J., 2002, Role of CD40 ligand in amyloidosis in transgenic Alzheimer’s mice. Nat. Neurosci. 5: 1288.PubMedGoogle Scholar
  119. Trollor, J.N. and Valenzuela, M.J., 2001, Brain ageing in the new millennium. Aust. NZ. J. Psychiat. 35: 788.Google Scholar
  120. Tuppo, E.E. and Arias, H.R., 2005, The role of inflammation in Alzheimer’s disease. Int. J. Biochem. Cell Biol. 37: 289.PubMedGoogle Scholar
  121. Vereker, E., Campbell, V., Roche, E., McEntee, E. and Lynch, M.A., 2000a, Lipopolysaccharide inhibts long-term potentiation in the rat dentate gyrus by activating caspase-1. J. Biol. Chem. 275: 26252.PubMedGoogle Scholar
  122. Vereker, E., O’Donnell, E. and Lynch, M.A., 2000b, The inhibitory effect of interleukin-1β on long-term potentiation is coupled with increased activity of stress-activated protein kinases. J. Neurosci. 20: 6811.PubMedGoogle Scholar
  123. Vilhardt, F., 2005, Microglia: phagocyte and glia cell. Int. J. Biochem. Cell Biol. 37: 17.PubMedGoogle Scholar
  124. Von Bernhardi, R. and Eugenin, J., 2004, Microglial reactivity to β-amyloid is modulated by astrocytes and pro-inflammatory factors. Brain Res. 1025: 186.PubMedGoogle Scholar
  125. Wang, Q., Rowan, M.J. and Anwyl, R., 2004, Beta-amyloid-mediated inhibition of NMDA receptor-dependent long-term potentiation induction involves activation of microglia and stimulation of inducible nitric oxide synthase and superoxide. J. Neurosci. 24: 6049.PubMedGoogle Scholar
  126. Wong, H.L., Costa, G.L., Lotze, M.T. and Wahl, S.M., 1993, Interleukin (IL) 4 differentially regulates monocyte IL-1 family gene expression and synthesis in vitro and in vivo. J. Exp. Med. 177: 775.PubMedGoogle Scholar
  127. Xia, Z., Dickens, M., Raingeaud, J., Davis, R.J. and Greenberg, M.E., 1995, Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270: 1326.PubMedGoogle Scholar
  128. Yang, D.D., Kuan, C., Whitmarsh, A.J., Rincon, M., Zheng, T.S., Davis, R.J., Rakic, P. and Flavell, R.A., 1997, Absence of excitotoxicity-induced apoptosis in hippocampus of mice lacking the Jnk 3 gene. Nature 389: 865.PubMedGoogle Scholar
  129. Yehuda, S., Rabinovitz, S., Carasso, R.L. and Mostofsky, D.I., 2002, The role of polyunsaturated fatty acids in restoring the aging neuronal membrane. Neurobiol. Aging 23: 843.PubMedGoogle Scholar
  130. Youssef, S., Stuve, O., Patarroyo, J.C., Ruiz, P.J., Radosevich, J.L., Hur, E.M., Bravo, M., Mitchell, D.J., Sobel, R.A., Steinman, L. and Zamvil, S.S., 2002, The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420: 78.PubMedGoogle Scholar
  131. Zemke, D. and Majid, A., 2004, The potential of minocylcine for neuroprotection in human neurological disease. Clin. Neuropharmacol. 27: 293.PubMedGoogle Scholar
  132. Zhang, Y., Appelkvist, E., Kristensson, K. and Dallner, G., 1996, The lipid compositions of different regions of rat brain during development and aging. Neurobiol. Aging 17: 869.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Marina Lynch
    • 1
  1. 1.Dep. PhysiolTrinity CollegeIreland

Personalised recommendations