Journal of Neural Transmission

, Volume 113, Issue 11, pp 1709–1715 | Cite as

TNF alpha affects the expression of GFAP and S100B: implications for Alzheimer’s disease

  • M. M. Edwards
  • S. R. Robinson


Neurodegenerative disorders such as Alzheimer’s disease are characterized by increased intracellular and extracellular concentrations of the astrocytic proteins glial fibrillary acidic protein (GFAP) and S100B. The present study examined the potential contribution of tumor necrosis factor alpha (TNFα) to these changes by measuring astrocyte viability along with the intracellular and extracellular expression of GFAP and S100B following exposure to this cytokine. Although TNFα did not affect astrocyte viability, the extracellular levels of both proteins were increased three-fold with associated reductions in immunocytochemical labeling.

Keywords: Astrocytes, TNFα, S100B, GFAP, Alzheimer’s disease 



Alzheimer’s disease


ammonium citrate


bovine serum albumin


Dulbeccos Modified Eagle Medium


fetal bovine serum


glial fibrillary acidic protein


lactate dehydrogenase


phosphate buffer


phosphate buffered saline


tumor necrosis factor alpha


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  1. Arcuri, C, Bianchi, R, Brozzi, F, Donato, R 2005S100b increases proliferation in PC12 neuronal cells and reduces their responsiveness to nerve growth factor via Akt activationJ Biol Chem28044024414PubMedCrossRefGoogle Scholar
  2. Barger, SW, Van Eldik, LJ, Mattson, MP 1995S100 beta protects hippocampal neurons from damage induced by glucose deprivationBrain Res677167170PubMedCrossRefGoogle Scholar
  3. Beach, TG, Walker, R, McGeer, EG 1989Patterns of gliosis in Alzheimer’s disease and aging cerebrumGlia2420436PubMedCrossRefGoogle Scholar
  4. Bhattacharyya, A, Oppenheim, RW, Prevette, D, Moore, BW, Brackenbury, R, Ratner, N 1992S100 is present in developing chicken neurons and Schwann cells and promotes motor neuron survival in vivoJ Neurobiol23451466PubMedCrossRefGoogle Scholar
  5. Bradford, MM 1976A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry72248254PubMedCrossRefGoogle Scholar
  6. Chao, CC, Hu, S, Ehrlich, L, Peterson, PK 1995Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate receptorsBrain Behav Immun9355365PubMedCrossRefGoogle Scholar
  7. Craft, JM, Watterson, DM, Frautschy, SA, Van Eldik, LJ 2004Aminopyridazines inhibit beta-amyloid-induced glial activation and neuronal damage in vivoNeurobiol Aging2512831292PubMedCrossRefGoogle Scholar
  8. Crols, R, Saerens, J, Noppe, M, Lowenthal, A 1986Increased GFAP levels in CSF as a marker of organicity in patients with Alzheimer’s disease and other types of irreversible chronic organic brain syndromeJ Neurol233157160PubMedCrossRefGoogle Scholar
  9. Delacourte, A 1990General and dramatic glial reaction in Alzheimer brainsNeurology403337PubMedCrossRefGoogle Scholar
  10. Donato, R 2003Intracellular and extracellular roles of S100 proteinsMicrosc Res Tech60540551PubMedCrossRefGoogle Scholar
  11. Eriksen, JL, Druse, MJ 2001Astrocyte-mediated trophic support of developing serotonin neurons: effects of ethanol, buspirone, and S100BBrain Res Dev Brain Res131915PubMedCrossRefGoogle Scholar
  12. Fillit, H, Ding, WH, Buee, L, Kalman, J, Altstiel, L, Lawlor, B, Wolf-Klein, G 1991Elevated circulating tumor necrosis factor levels in Alzheimer’s diseaseNeurosci Lett129318320PubMedCrossRefGoogle Scholar
  13. Fine, SM, Angel, RA, Perry, SW, Epstein, LG, Rothstein, JD, Dewhurst, S, Gelbard, HA 1996Tumor necrosis factor alpha inhibits glutamate uptake by primary human astrocytes. Implications for pathogenesis of HIV-1 dementiaJ Biol Chem2711530315306PubMedCrossRefGoogle Scholar
  14. Fukuyama, R, Izumoto, T, Fushiki, S 2001The cerebrospinal fluid level of glial fibrillary acidic protein is increased in cerebrospinal fluid from Alzheimer’s disease patients and correlates with severity of dementiaEur Neurol463538PubMedCrossRefGoogle Scholar
  15. Grammas, P, Ovase, R 2001Inflammatory factors are elevated in brain microvessels in Alzheimer’s diseaseNeurobiol Aging22837842PubMedCrossRefGoogle Scholar
  16. Green, AJ, Harvey, RJ, Thompson, EJ, Rossor, MN 1997Increased S100beta in the cerebrospinal fluid of patients with frontotemporal dementiaNeurosci Lett23558PubMedCrossRefGoogle Scholar
  17. Griffin, WS, Stanley, LC, Ling, C, White, L, MacLeod, V, Perrot, LJ, White, CL,3rd, Araoz, C 1989Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer diseaseProc Natl Acad Sci USA8676117615PubMedCrossRefGoogle Scholar
  18. Griffin, WS, Sheng, JG, McKenzie, JE, Royston, MC, Gentleman, SM, Brumback, RA, Cork, LC, Del Bigio, MR, Roberts, GW, Mrak, RE 1998Life-long overexpression of S100beta in Down’s syndrome: implications for Alzheimer pathogenesisNeurobiol Aging19401405PubMedCrossRefGoogle Scholar
  19. Halliday, G, Robinson, SR, Shepherd, C, Kril, J 2000Alzheimer’s disease and inflammation: a review of cellular and therapeutic mechanismsClin Exp Pharmacol P2718CrossRefGoogle Scholar
  20. Harpin, ML, Delaere, P, Javoy-Agid, F, Bock, E, Jacque, C, Delpech, B, Villarroya, H, Duyckaerts, C, Hauw, JJ, Baumann, N 1990Glial fibrillary acidic protein and beta A4 protein deposits in temporal lobe of aging brain and senile dementia of the Alzheimer type: relation with the cognitive state and with quantitative studies of senile plaques and neurofibrillary tanglesJ Neurosci Res27587594PubMedCrossRefGoogle Scholar
  21. Hu, S, Sheng, WS, Ehrlich, LC, Peterson, PK, Chao, CC 2000Cytokine effects on glutamate uptake by human astrocytesNeuroimmunomodulation7153159PubMedCrossRefGoogle Scholar
  22. Kobayashi, K, Hayashi, M, Nakano, H, Fukutani, Y, Sasaki, K, Shimazaki, M, Koshino, Y 2002Apoptosis of astrocytes with enhanced lysosomal activity and oligodendrocytes in white matter lesions in Alzheimer’s diseaseNeuropathol Appl Neurobiol28238251PubMedCrossRefGoogle Scholar
  23. Le Prince, G, Delaere, P, Fages, C, Lefrancois, T, Touret, M, Salanon, M, Tardy, M 1995Glutamine synthetase (GS) expression is reduced in senile dementia of the Alzheimer typeNeurochem Res20859862PubMedCrossRefGoogle Scholar
  24. Li, WP, Chan, WY, Lai, HW, Yew, DT 1997Terminal dUTP nick end labeling (TUNEL) positive cells in the different regions of the brain in normal aging and Alzheimer patientsJ Mol Neurosci87582PubMedGoogle Scholar
  25. Li, Y, Wang, J, Sheng, JG, Liu, L, Barger, SW, Jones, RA, Van Eldik, LJ, Mrak, RE, Griffin, WS 1998S100 beta increases levels of beta-amyloid precursor protein and its encoding mRNA in rat neuronal culturesJ Neurochem7114211428PubMedCrossRefGoogle Scholar
  26. Liao, SL, Chen, CJ 2001Differential effects of cytokines and redox potential on glutamate uptake in rat cortical glial culturesNeurosci Lett299113116PubMedCrossRefGoogle Scholar
  27. Liddell, JR, Robinson, SR, Dringen, R 2004Endogenous glutathione and catalase protect rat astrocytes from iron-mediated toxicity of hydrogen peroxideNeurosci Lett364164167PubMedCrossRefGoogle Scholar
  28. Mark, KS, Miller, DW 1999Increased permeability of primary cultured brain microvessel endothelial cell monolayers following TNF-alpha exposureLife Sci6419411953PubMedCrossRefGoogle Scholar
  29. Marshak, DR 1990S100 beta as a neurotrophic factorProg Brain Res86169181PubMedCrossRefGoogle Scholar
  30. Marshak, DR, Pecse, SA, Stanley, LC, Griffin, WS 1991Increased S100 beta neurotrophic activity in Alzheimer’s disease temporal lobeNeurobiol Aging1317CrossRefGoogle Scholar
  31. McCarthy, KD, de Vellis, J 1980Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissueJ Cell Biol85890902PubMedCrossRefGoogle Scholar
  32. Mrak, RE, Griffin, WS 2001The role of activated astrocytes and of the neurotrophic cytokine S100B in the pathogenesis of Alzheimer’s diseaseNeurobiol Aging22915922PubMedCrossRefGoogle Scholar
  33. Mrak, RE, Sheng, JG, Griffin, WS 1996Correlation of astrocytic S100 beta expression with dystrophic neurites in amyloid plaques of Alzheimer’s diseaseJ Neuropathol Exp Neurol55273279PubMedGoogle Scholar
  34. Murphy, GM,Jr, Lee, YL, Jia, XC, Yu, AC, Majewska, A, Song, Y, Schmidt, K, Eng, LF 1995Tumor necrosis factor-alpha and basic fibroblast growth factor decrease glial fibrillary acidic protein and its encoding mRNA in astrocyte cultures and glioblastoma cellsJ Neurochem6527162724PubMedCrossRefGoogle Scholar
  35. Noppe, M, Crols, R, Andries, D, Lowenthal, A 1986Determination in human cerebrospinal fluid of glial fibrillary acidic protein, S-100 and myelin basic protein as indices of non-specific or specific central nervous tissue pathologyClin Chim Acta155143150PubMedCrossRefGoogle Scholar
  36. Peskind, ER, Griffin, WS, Akama, KT, Raskind, MA, Van Eldik, LJ 2001Cerebrospinal fluid S100B is elevated in the earlier stages of Alzheimer’s diseaseNeurochem Int39409413PubMedCrossRefGoogle Scholar
  37. Petzold, A, Jenkins, R, Watt, HC, Green, AJ, Thompson, EJ, Keir, G, Fox, NC, Rossor, MN 2003Cerebrospinal fluid S100B correlates with brain atrophy in Alzheimer’s diseaseNeurosci Lett336167170PubMedCrossRefGoogle Scholar
  38. Robinson, S, Noone, D, Kril, J, Halliday, G 1995Most amyloid plaques contain ferritin-rich cellsAlzheimer’s Research1340344Google Scholar
  39. Robinson, SR 2001Changes in the cellular distribution of glutamine synthetase in Alzheimer’s diseaseJ Neurosci Res66972980PubMedCrossRefGoogle Scholar
  40. Selmaj, K, Shafit-Zagardo, B, Aquino, DA, Farooq, M, Raine, CS, Norton, WT, Brosnan, CF 1991Tumor necrosis factor-induced proliferation of astrocytes from mature brain is associated with down-regulation of glial fibrillary acidic protein mRNAJ Neurochem57823830PubMedCrossRefGoogle Scholar
  41. Selmaj, KW, Farooq, M, Norton, WT, Raine, CS, Brosnan, CF 1990Proliferation of astrocytes in vitro in response to cytokines. A primary role for tumor necrosis factorJ Immunol144129135PubMedGoogle Scholar
  42. Sheng, JG, Mrak, RE, Griffin, WS 1994S100 beta protein expression in Alzheimer disease: potential role in the pathogenesis of neuritic plaquesJ Neurosci Res39398404PubMedCrossRefGoogle Scholar
  43. Sheng, JG, Ito, K, Skinner, RD, Mrak, RE, Rovnaghi, CR, Van Eldik, LJ, Griffin, WS 1996In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesisNeurobiol Aging17761766PubMedCrossRefGoogle Scholar
  44. Smale, G, Nichols, NR, Brady, DR, Finch, CE, Horton, WE,Jr 1995Evidence for apoptotic cell death in Alzheimer’s diseaseExp Neurol133225230PubMedCrossRefGoogle Scholar
  45. Tarkowski, E 2002Cytokines in dementiasCurr Drug Targets Inflamm Allergy1193200PubMedCrossRefGoogle Scholar
  46. Van Eldik, LJ, Griffin, WS 1994S100 beta expression in Alzheimer’s disease: relation to neuropathology in brain regionsBiochim Biophys Acta1223398403PubMedCrossRefGoogle Scholar
  47. Van Eldik, LJ, Zimmer, DB 1987Secretion of S-100 from rat C6 glioma cellsBrain Res436367370PubMedCrossRefGoogle Scholar
  48. Vijayan, VK, Geddes, JW, Anderson, KJ, Chang-Chui, H, Ellis, WG, Cotman, CW 1991Astrocyte hypertrophy in the Alzheimer’s disease hippocampal formationExp Neurol1127278PubMedCrossRefGoogle Scholar
  49. Wallin, A, Blennow, K, Rosengren, LE 1996Glial fibrillary acidic protein in the cerebrospinal fluid of patients with dementiaDementia7267272PubMedGoogle Scholar
  50. Whitaker-Azmitia, PM, Murphy, R, Azmitia, EC 1990Stimulation of astroglial 5-HT1A receptors releases the serotonergic growth factor, protein S-100, and alters astroglial morphologyBrain Res528155158PubMedCrossRefGoogle Scholar
  51. Willoughby, KA, Kleindienst, A, Muller, C, Chen, T, Muir, JK, Ellis, EF 2004S100B protein is released by in vitro trauma and reduces delayed neuronal injuryJ Neurochem9112841291PubMedCrossRefGoogle Scholar
  52. Winningham-Major, F, Staecker, JL, Barger, SW, Coats, S, Van Eldik, LJ 1989Neurite extension and neuronal survival activities of recombinant S100 beta proteins that differ in the content and position of cysteine residuesJ Cell Biol10930633071PubMedCrossRefGoogle Scholar
  53. Ye, ZC, Sontheimer, H 1996Cytokine modulation of glial glutamate uptake: a possible involvement of nitric oxideNeuroreport721812185PubMedGoogle Scholar
  54. Zhang, L, Zhao, W, Li, B, Alkon, DL, Barker, JL, Chang, YH, Wu, M, Rubinow, DR 2000TNF-alpha induced over-expression of GFAP is associated with MAPKsNeuroreport11409412PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • M. M. Edwards
    • 1
  • S. R. Robinson
    • 1
  1. 1.School of Psychology, Psychiatry and Psychological Medicine, Monash UniversityClaytonAustralia

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