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Enhanced Expression of Glia Maturation Factor Correlates with Glial Activation in the Brain of Triple Transgenic Alzheimer’s Disease Mice

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Abstract

We previously demonstrated that glia maturation factor (GMF), a brain specific protein, isolated, sequenced and cloned in our laboratory, induce expression of proinflammatory cytokines and chemokines in the central nervous system. We also reported that the up-regulation of GMF in astrocytes leads to the destruction of neurons suggesting a novel pathway of GMF-mediated cytotoxicity of brain cells, and implicated its involvement in the pathogenesis of inflammatory neurodegenerative diseases. In the present study, we examined the expressions of GMF in triple-transgenic Alzheimer’s disease (3xTg-AD) mice. Our results show a 13-fold up-regulation of GMF and 8–12-fold up-regulation of proinflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1β, interferon gamma (IFN-γ), and chemokine (C–C motif) ligand 2 (CCL2) and C–X–C motif chemokine 10 (CXCL10/IP-10) mRNA as determined by quantitative real-time RT-PCR in the brain of 3xTg-AD mice as compared to non-transgenic (Non-Tg) mice. In conclusion, the increase in GMF and cytokine/chemokine expression was correlated with reactive glial fibrillary acidic protein positive astrocytes and ionized calcium binding adaptor molecule 1 (Iba-1)-positive microglia in 3xTg-AD mice.

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Abbreviations

CCL2:

Chemokine (C–C motif) ligand 2

CXCL10:

C–X–C motif chemokine 10

CNS:

Central nervous system

ELISA:

Enzyme-linked immunosorbent assay

GFAP:

Glial fibriallary acidic protein

IFN-γ:

Interferon-gamma

IL-1:

Interleukin-1

Non-Tg:

Non-transgenic mice

GMF:

Glia maturation factor

Real-time PCR:

Real-time polymerase chain reaction

3xTg-AD mice:

Triple transgenic Alzheimer’s disease

TNF-α:

Tumor necrosis factor-alpha

References

  1. Thangavel R, Van Hoesen GW, Zaheer A (2008) Posterior parahippocampal gyrus pathology in Alzheimer’s disease. Neuroscience 154:667–676

    Article  PubMed  CAS  Google Scholar 

  2. Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, Duyckaerts C, Frosch MP, Haroutunian V, Hof PR, Hulette CM, Hyman BT, Iwatsubo T, Jellinger KA, Jicha GA, Kovari E, Kukull WA, Leverenz JB, Love S, Mackenzie IR, Mann DM, Masliah E, McKee AC, Montine TJ, Morris JC, Schneider JA, Sonnen JA, Thal DR, Trojanowski JQ, Troncoso JC, Wisniewski T, Woltjer RL, Beach TG (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362–381

    Article  PubMed  Google Scholar 

  3. Hall AM, Roberson ED (2012) Mouse models of Alzheimer’s disease. Brain Res Bull 88:3–12

    Article  PubMed  CAS  Google Scholar 

  4. Roltsch E, Holcomb L, Young KA, Marks A, Zimmer DB (2010) PSAPP mice exhibit regionally selective reductions in gliosis and plaque deposition in response to S100B ablation. J Neuroinflammation 7:78

    Article  PubMed  Google Scholar 

  5. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F et al (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373:523–527

    Article  PubMed  CAS  Google Scholar 

  6. Johnson-Wood K, Lee M, Motter R, Hu K, Gordon G, Barbour R, Khan K, Gordon M, Tan H, Games D, Lieberburg I, Schenk D, Seubert P, McConlogue L (1997) Amyloid precursor protein processing and A beta42 deposition in a transgenic mouse model of Alzheimer disease. Proc Natl Acad Sci USA 94:1550–1555

    Article  PubMed  CAS  Google Scholar 

  7. Mori T, Koyama N, Arendash GW, Horikoshi-Sakuraba Y, Tan J, Town T (2010) Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer’s disease. Glia 58:300–314

    PubMed  Google Scholar 

  8. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421

    Article  PubMed  CAS  Google Scholar 

  9. Lim R, Zaheer A, Lane WS (1990) Complete amino acid sequence of bovine glia maturation factor beta. Proc Natl Acad Sci USA 87:5233–5237

    Article  PubMed  CAS  Google Scholar 

  10. Lim R, Miller JF, Zaheer A (1989) Purification and characterization of glia maturation factor beta: a growth regulator for neurons and glia. Proc Natl Acad Sci USA 86:3901–3905

    Article  PubMed  CAS  Google Scholar 

  11. Zaheer S, Thangavel R, Sahu SK, Zaheer A (2011) Augmented expression of glia maturation factor in Alzheimer’s disease. Neuroscience 194:227–233

    Article  PubMed  CAS  Google Scholar 

  12. Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM (2005) Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45:675–688

    Article  PubMed  CAS  Google Scholar 

  13. Zaheer S, Wu Y, Yang X, Ahrens M, Sahu SK, Zaheer A (2012) Clinical course of myelin oligodendrocyte glycoprotein 35–55 induced experimental autoimmune encephalomyelitis is aggravated by glia maturation factor. Neurochem Int 60:215–219

    Article  PubMed  CAS  Google Scholar 

  14. Thangavel R, Sahu SK, Van Hoesen GW, Zaheer A (2008) Modular and laminar pathology of Brodmann’s area 37 in Alzheimer’s disease. Neuroscience 152:50–55

    Article  PubMed  CAS  Google Scholar 

  15. Thangavel R, Sahu SK, Van Hoesen GW, Zaheer A (2009) Loss of nonphosphorylated neurofilament immunoreactivity in temporal cortical areas in Alzheimer’s disease. Neuroscience 160:427–433

    Article  PubMed  CAS  Google Scholar 

  16. Thangavel R, Van Hoesen GW, Zaheer A (2009) The abnormally phosphorylated tau lesion of early Alzheimer’s disease. Neurochem Res 34:118–123

    Article  PubMed  CAS  Google Scholar 

  17. Zaheer A, Zhong W, Lim R (1995) Expression of mRNAs of multiple growth factors and receptors by neuronal cell lines: detection with RT-PCR. Neurochem Res 20:1457–1463

    Article  PubMed  CAS  Google Scholar 

  18. Zaheer A, Zaheer S, Sahu SK, Knight S, Khosravi H, Mathur SN, Lim R (2007) A novel role of glia maturation factor: induction of granulocyte-macrophage colony-stimulating factor and pro-inflammatory cytokines. J Neurochem 101:364–376

    Article  PubMed  CAS  Google Scholar 

  19. Zaheer A, Zhong W, Uc EY, Moser DR, Lim R (1995) Expression of mRNAs of multiple growth factors and receptors by astrocytes and glioma cells: detection with reverse transcription-polymerase chain reaction. Cell Mol Neurobiol 15:221–237

    Article  PubMed  CAS  Google Scholar 

  20. Lim R, Zaheer A (1995) Phorbol ester stimulates rapid intracellular phosphorylation of glia maturation factor. Biochem Biophys Res Commun 211:928–934

    Article  PubMed  CAS  Google Scholar 

  21. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159

    Article  PubMed  CAS  Google Scholar 

  22. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  23. Eikelenboom P, Zhan SS, van Gool WA, Allsop D (1994) Inflammatory mechanisms in Alzheimer’s disease. Trends Pharmacol Sci 15:447–450

    Article  PubMed  CAS  Google Scholar 

  24. Kim SU, de Vellis J (2005) Microglia in health and disease. J Neurosci Res 81:302–313

    Article  PubMed  CAS  Google Scholar 

  25. Garden GA, Moller T (2006) Microglia biology in health and disease. J Neuroimmune Pharmacol 1:127–137

    Article  PubMed  Google Scholar 

  26. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934

    Article  PubMed  CAS  Google Scholar 

  27. Farfara D, Lifshitz V, Frenkel D (2008) Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer’s disease. J Cell Mol Med 12:762–780

    Article  PubMed  CAS  Google Scholar 

  28. Block ML, Hong JS (2005) Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 76:77–98

    Article  PubMed  CAS  Google Scholar 

  29. Kaplan R, Zaheer A, Jaye M, Lim R (1991) Molecular cloning and expression of biologically active human glia maturation factor-beta. J Neurochem 57:483–490

    Article  PubMed  CAS  Google Scholar 

  30. Lim R, Zaheer A (1991) Structure and function of glia maturation factor beta. Adv Exp Med Biol 296:161–164

    Article  PubMed  CAS  Google Scholar 

  31. Lim R, Zaheer A (1996) In vitro enhancement of p38 mitogen-activated protein kinase activity by phosphorylated glia maturation factor. J Biol Chem 271:22953–22956

    Article  PubMed  CAS  Google Scholar 

  32. Lim R, Zaheer A, Yorek MA, Darby CJ, Oberley LW (2000) Activation of nuclear factor-kappaB in C6 rat glioma cells after transfection with glia maturation factor. J Neurochem 74:596–602

    Article  PubMed  CAS  Google Scholar 

  33. Zaheer A, Lim R (1996) In vitro inhibition of MAP kinase (ERK1/ERK2) activity by phosphorylated glia maturation factor (GMF). Biochemistry 35:6283–6288

    Article  PubMed  CAS  Google Scholar 

  34. Zaheer A, Lim R (1997) Protein kinase A (PKA)- and protein kinase C-phosphorylated glia maturation factor promotes the catalytic activity of PKA. J Biol Chem 272:5183–5186

    Article  PubMed  CAS  Google Scholar 

  35. Zaheer A, Sahu SK, Wu Y, Haas J, Lee K, Yang B (2007) Diminished cytokine and chemokine expression in the central nervous system of GMF-deficient mice with experimental autoimmune encephalomyelitis. Brain Res 1144:239–247

    Article  PubMed  CAS  Google Scholar 

  36. Zaheer A, Zaheer S, Sahu SK, Yang B, Lim R (2007) Reduced severity of experimental autoimmune encephalomyelitis in GMF-deficient mice. Neurochem Res 32:39–47

    Article  PubMed  CAS  Google Scholar 

  37. Zaheer S, Wu Y, Sahu SK, Zaheer A (2011) Suppression of neuro inflammation in experimental autoimmune encephalomyelitis by glia maturation factor antibody. Brain Res 1373:230–239

    Article  PubMed  CAS  Google Scholar 

  38. Zaheer A, Zaheer S, Thangavel R, Wu Y, Sahu SK, Yang B (2008) Glia maturation factor modulates beta-amyloid-induced glial activation, inflammatory cytokine/chemokine production and neuronal damage. Brain Res 1208:192–203

    Article  PubMed  CAS  Google Scholar 

  39. Zaheer S, Wu Y, Sahu SK, Zaheer A (2010) Overexpression of glia maturation factor reinstates susceptibility to myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in glia maturation factor deficient mice. Neurobiol Dis 40:593–598

    Article  PubMed  CAS  Google Scholar 

  40. Thangavel R, Stolmeier D, Yang X, Anantharam P, Zaheer A (2012) Expression of Glia maturation factor in neuropathological lesions of Alzheimer’s disease. Neuropathol Appl Neurobiol 38:572–581

    Google Scholar 

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Acknowledgments

We thank Scott Knight, Ashna Zaheer, and Marcus Ahrens for excellent technical help. 3xTg-AD mice were from Dr. Frank M. LaFerla, University of California, Irvine, obtained from Dr. Gloria Lee, University of Iowa. This work was supported by the Department of Veterans Affairs Merit Review award (to A.Z.) and by the National Institute of Neurological Disorders and Stroke grant NS-47145 (to A.Z.).

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Authors and Affiliations

  1. Veterans Affair Health Care System, Iowa City, IA, USA

    Ramasamy Thangavel, Duraisamy Kempuraj & Asgar Zaheer

  2. Department of Neurology, The University of Iowa, 200 Hawkins Drive, Iowa City, IA, 52242, USA

    Smita Zaheer, Ramasamy Thangavel, Yanghong Wu, Mohammad Moshahid Khan, Duraisamy Kempuraj & Asgar Zaheer

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  1. Smita Zaheer
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  2. Ramasamy Thangavel
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  3. Yanghong Wu
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  4. Mohammad Moshahid Khan
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  5. Duraisamy Kempuraj
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  6. Asgar Zaheer
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Correspondence to Asgar Zaheer.

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Zaheer, S., Thangavel, R., Wu, Y. et al. Enhanced Expression of Glia Maturation Factor Correlates with Glial Activation in the Brain of Triple Transgenic Alzheimer’s Disease Mice. Neurochem Res 38, 218–225 (2013). https://doi.org/10.1007/s11064-012-0913-z

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  • DOI: https://doi.org/10.1007/s11064-012-0913-z

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