Advertisement

Metabotropic glutamate receptor subtype 5 is altered in LPS-induced murine neuroinflammation model and in the brains of AD and ALS patients

  • Adrienne Müller Herde
  • Roger Schibli
  • Markus Weber
  • Simon M. Ametamey
Original Article

Abstract

Purpose

The aim of the present study was to determine the expression levels of mGluR5 in different mouse strains after induction of neuroinflammation by lipopolysaccharide (LPS) challenge and in the brains of patients with Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) post mortem to investigate mGluR5 expression in human neurodegenerative diseases.

Methods

C57BL/6 and CD1 mice were injected intraperitoneally with either 10 mg/kg LPS or saline. mGluR5 and TSPO mRNA levels were measured after 1 and 5 days by qPCR, and mGluR5 protein levels were determined by PET imaging with the mGluR5-specific radiotracer [18F]PSS232. mGluR5 expression was evaluated in the post-mortem brain slices from AD and ALS patients using in vitro autoradiography.

Results

mGluR5 and TSPO mRNA levels were increased in brains of C57BL/6 and CD1 mice 1 day after LPS treatment and remained significantly increased after 5 days in C57BL/6 mice but not in CD1 mice. Brain PET imaging with [18F]PSS232 confirmed increased mGluR5 levels in the brains of both mouse strains 1 day after LPS treatment. After 5 days, mGluR5 levels in CD1 mice declined to the levels in vehicle-treated mice but remained high in C57BL/6 mice. Autoradiograms revealed a severalfold higher binding of [18F]PSS232 in post-mortem brain slices from AD and ALS patients compared with the binding in control brains.

Conclusion

LPS-induced neuroinflammation increased mGluR5 levels in mouse brain and is dependent on the mouse strain and time after LPS treatment. mGluR5 levels were also increased in human AD and ALS brains in vitro. PET imaging of mGluR5 levels could potentially be used to diagnose and monitor therapy outcomes in patients with AD and ALS.

Keywords

Metabotropic glutamate receptor subtype 5 [18F]PSS232 Positron emission tomography Neuroinflammation Neurodegenerative disease Lipopolysaccharide 

Notes

Acknowledgments

We acknowledge Claudia Keller for LPS administrations and animal care and for performing the PET/CT scans. We thank Bruno Mancosu for [18F]PSS232 production and Dr. Linjing Mu for her support in radiolabelling and quality control as well as for fruitful discussions. We thank Prof. Stefanie D. Krämer for rewarding discussions during the study. We acknowledge Dr. Markus Margelisch (Cantonal Hospital St. Gallen, Switzerland) for providing the human ALS brain tissue. We thank Prof. Julian Romero (University Hospital Alcorcón, Spain), Brain Bank (Hospital Universitario Fundación Alcorcón, Madrid, Spain) and Prof. Catriona McLean with Prof. Colin Masters (Victorian Brain Bank Network, Melbourne, Australia) for providing the Alzheimer’s disease brain slices. We acknowledge the support of the Scientific Center for Optical and Electron Microscopy (ScopeM) of ETH Zurich.

Compliance with ethical standards

Conflicts of interest

None.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

All procedures performed in studies involving human tissue were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

References

  1. 1.
    Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neurodegenerative diseases. Immunology. 2010;129:154–69.  https://doi.org/10.1111/j.1365-2567.2009.03225.x.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Jellinger KA. Basic mechanisms of neurodegeneration: a critical update. J Cell Mol Med. 2010;14:457–87.  https://doi.org/10.1111/j.1582-4934.2010.01010.x.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Tohidpour A, Morgun AV, Boitsova EB, Malinovskaya NA, Martynova GP, Khilazheva ED, et al. Neuroinflammation and infection: molecular mechanisms associated with dysfunction of neurovascular unit. Front Cell Infect Microbiol. 2017;7:276.  https://doi.org/10.3389/fcimb.2017.00276.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Nazem A, Sankowski R, Bacher M, Al-Abed Y. Rodent models of neuroinflammation for Alzheimer’s disease. J Neuroinflammation. 2015;12:74.  https://doi.org/10.1186/s12974-015-0291-y.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Catorce MN, Gevorkian G. LPS-induced murine neuroinflammation model: main features and suitability for pre-clinical assessment of nutraceuticals. Curr Neuropharmacol. 2016;14:155–64.CrossRefGoogle Scholar
  6. 6.
    Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer’s disease, role of cytokines. ScientificWorldJournal. 2012;2012:756357.  https://doi.org/10.1100/2012/756357.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Nadeau S, Rivest S. Effects of circulating tumor necrosis factor on the neuronal activity and expression of the genes encoding the tumor necrosis factor receptors (p55 and p75) in the rat brain: a view from the blood-brain barrier. Neuroscience. 1999;93:1449–64.CrossRefGoogle Scholar
  8. 8.
    Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007;55:453–62.  https://doi.org/10.1002/glia.20467.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ifuku M, Katafuchi T, Mawatari S, Noda M, Miake K, Sugiyama M, et al. Anti-inflammatory/anti-amyloidogenic effects of plasmalogens in lipopolysaccharide-induced neuroinflammation in adult mice. J Neuroinflammation. 2012;9:197.  https://doi.org/10.1186/1742-2094-9-197.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Sheng JG, Bora SH, Xu G, Borchelt DR, Price DL, Koliatsos VE. Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiol Dis. 2003;14:133–45.CrossRefGoogle Scholar
  11. 11.
    Crawshaw AA, Robertson NP. The role of TSPO PET in assessing neuroinflammation. J Neurol. 2017;264:1825–7.  https://doi.org/10.1007/s00415-017-8565-1.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Drouin-Ouellet J, Brownell AL, Saint-Pierre M, Fasano C, Emond V, Trudeau LE, et al. Neuroinflammation is associated with changes in glial mGluR5 expression and the development of neonatal excitotoxic lesions. Glia. 2011;59:188–99.  https://doi.org/10.1002/glia.21086.CrossRefPubMedGoogle Scholar
  13. 13.
    Piers TM, Kim DH, Kim BC, Regan P, Whitcomb DJ, Cho K. Translational concepts of mGluR5 in synaptic diseases of the brain. Front Pharmacol. 2012;3:199.  https://doi.org/10.3389/fphar.2012.00199.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Byrnes KR, Loane DJ, Stoica BA, Zhang J, Faden AI. Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury. J Neuroinflammation. 2012;9:43.  https://doi.org/10.1186/1742-2094-9-43.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Awad H, Hubert GW, Smith Y, Levey AI, Conn PJ. Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J Neurosci. 2000;20:7871–9.CrossRefGoogle Scholar
  16. 16.
    Jong YJ, Kumar V, O’Malley KL. Intracellular metabotropic glutamate receptor 5 (mGluR5) activates signalling cascades distinct from cell surface counterparts. J Biol Chem. 2009;284:35827–38.  https://doi.org/10.1074/jbc.M109.046276.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Abushik PA, Niittykoski M, Giniatullina R, Shakirzyanova A, Bart G, Fayuk D, et al. The role of NMDA and mGluR5 receptors in calcium mobilization and neurotoxicity of homocysteine in trigeminal and cortical neurons and glial cells. J Neurochem. 2014;129:264–74.  https://doi.org/10.1111/jnc.12615.CrossRefPubMedGoogle Scholar
  18. 18.
    Luyt K, Varadi A, Durant CF, Molnar E. Oligodendroglial metabotropic glutamate receptors are developmentally regulated and involved in the prevention of apoptosis. J Neurochem. 2006;99:641–56.  https://doi.org/10.1111/j.1471-4159.2006.04103.x.CrossRefPubMedGoogle Scholar
  19. 19.
    Milicevic Sephton S, Müller Herde A, Mu L, Keller C, Rudisuhli S, Auberson Y, et al. Preclinical evaluation and test-retest studies of [(18)F]PSS232, a novel radioligand for targeting metabotropic glutamate receptor 5 (mGlu5). Eur J Nucl Med Mol Imaging. 2015;42:128–37.  https://doi.org/10.1007/s00259-014-2883-7.CrossRefGoogle Scholar
  20. 20.
    Müller Herde A, Keller C, Milicevic Sephton S, Mu L, Schibli R, Ametamey SM, et al. Quantitative positron emission tomography of mGluR5 in rat brain with [(18) F]PSS232 at minimal invasiveness and reduced model complexity. J Neurochem. 2015;133:330–42.  https://doi.org/10.1111/jnc.13001.CrossRefPubMedGoogle Scholar
  21. 21.
    Arsenault D, Coulombe K, Zhu A, Gong C, Kil KE, Choi JK, et al. Loss of metabotropic glutamate receptor 5 function on peripheral benzodiazepine receptor in mice prenatally exposed to LPS. PLoS One. 2015;10:e0142093.  https://doi.org/10.1371/journal.pone.0142093.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ametamey SM, Treyer V, Streffer J, Wyss MT, Schmidt M, Blagoev M, et al. Human PET studies of metabotropic glutamate receptor subtype 5 with 11C-ABP688. J Nucl Med. 2007;48:247–52.PubMedGoogle Scholar
  23. 23.
    Ferraguti F, Corti C, Valerio E, Mion S, Xuereb J. Activated astrocytes in areas of kainate-induced neuronal injury upregulate the expression of the metabotropic glutamate receptors 2/3 and 5. Exp Brain Res. 2001;137:1–11.CrossRefGoogle Scholar
  24. 24.
    D’Ascenzo M, Fellin T, Terunuma M, Revilla-Sanchez R, Meaney DF, Auberson YP, et al. mGluR5 stimulates gliotransmission in the nucleus accumbens. Proc Natl Acad Sci U S A. 2007;104:1995–2000.  https://doi.org/10.1073/pnas.0609408104.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Pin JP, Duvoisin R. The metabotropic glutamate receptors: structure and functions. Neuropharmacology. 1995;34:1–26.CrossRefGoogle Scholar
  26. 26.
    Endoh T. Characterization of modulatory effects of postsynaptic metabotropic glutamate receptors on calcium currents in rat nucleus tractus solitarius. Brain Res. 2004;1024:212–24.  https://doi.org/10.1016/j.brainres.2004.07.074.CrossRefPubMedGoogle Scholar
  27. 27.
    Mannaioni G, Marino MJ, Valenti O, Traynelis SF, Conn PJ. Metabotropic glutamate receptors 1 and 5 differentially regulate CA1 pyramidal cell function. J Neurosci. 2001;21:5925–34.CrossRefGoogle Scholar
  28. 28.
    Kumar A, Dhull DK, Mishra PS. Therapeutic potential of mGluR5 targeting in Alzheimer’s disease. Front Neurosci. 2015;9:215.  https://doi.org/10.3389/fnins.2015.00215.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    De Maio A, Mooney ML, Matesic LE, Paidas CN, Reeves RH. Genetic component in the inflammatory response induced by bacterial lipopolysaccharide. Shock. 1998;10:319–23.CrossRefGoogle Scholar
  30. 30.
    Hopkins W, Gendron-Fitzpatrick A, McCarthy DO, Haine JE, Uehling DT. Lipopolysaccharide-responder and nonresponder C3H mouse strains are equally susceptible to an induced Escherichia coli urinary tract infection. Infect Immun. 1996;64:1369–72.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Yang IV, Rutledge HR, Yang J, Warg LA, Sevilla SD, Schwartz DA. A locus on chromosome 9 is associated with differential response of 129S1/SvImJ and FVB/NJ strains of mice to systemic LPS. Mamm Genome. 2011;22:518–29.  https://doi.org/10.1007/s00335-011-9340-8.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lopes PC. LPS and neuroinflammation: a matter of timing. Inflammopharmacology. 2016;24:291–3.  https://doi.org/10.1007/s10787-016-0283-2.CrossRefPubMedGoogle Scholar
  33. 33.
    Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004;172:2731–8.CrossRefGoogle Scholar
  34. 34.
    Brownell AL, Kuruppu D, Kil KE, Jokivarsi K, Poutiainen P, Zhu A, et al. PET imaging studies show enhanced expression of mGluR5 and inflammatory response during progressive degeneration in ALS mouse model expressing SOD1-G93A gene. J Neuroinflammation. 2015;12:217.  https://doi.org/10.1186/s12974-015-0439-9.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Vermeiren C, Hemptinne I, Vanhoutte N, Tilleux S, Maloteaux JM, Hermans E. Loss of metabotropic glutamate receptor-mediated regulation of glutamate transport in chemically activated astrocytes in a rat model of amyotrophic lateral sclerosis. J Neurochem. 2006;96:719–31.  https://doi.org/10.1111/j.1471-4159.2005.03577.x.CrossRefPubMedGoogle Scholar
  36. 36.
    Fang XT, Eriksson J, Antoni G, Yngve U, Cato L, Lannfelt L, et al. Brain mGluR5 in mice with amyloid beta pathology studied with in vivo [(11)C]ABP688 PET imaging and ex vivo immunoblotting. Neuropharmacology. 2017;113:293–300.  https://doi.org/10.1016/j.neuropharm.2016.10.009.CrossRefPubMedGoogle Scholar
  37. 37.
    Lee M, Lee HJ, Park IS, Park JA, Kwon YJ, Ryu YH, et al. Abeta pathology downregulates brain mGluR5 density in a mouse model of Alzheimer. Neuropharmacology. 2018;133:512–7.  https://doi.org/10.1016/j.neuropharm.2018.02.003.CrossRefPubMedGoogle Scholar
  38. 38.
    Lee HG, Zhu X, O’Neill MJ, Webber K, Casadesus G, Marlatt M, et al. The role of metabotropic glutamate receptors in Alzheimer’s disease. Acta Neurobiol Exp (Wars). 2004;64:89–98.Google Scholar
  39. 39.
    Byrnes KR, Stoica B, Loane DJ, Riccio A, Davis MI, Faden AI. Metabotropic glutamate receptor 5 activation inhibits microglial associated inflammation and neurotoxicity. Glia. 2009;57:550–60.  https://doi.org/10.1002/glia.20783.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Loane DJ, Stoica BA, Pajoohesh-Ganji A, Byrnes KR, Faden AI. Activation of metabotropic glutamate receptor 5 modulates microglial reactivity and neurotoxicity by inhibiting NADPH oxidase. J Biol Chem. 2009;284:15629–39.  https://doi.org/10.1074/jbc.M806139200.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Caraci F, Nicoletti F, Copani A. Metabotropic glutamate receptors: the potential for therapeutic applications in Alzheimer’s disease. Curr Opin Pharmacol. 2018;38:1–7.  https://doi.org/10.1016/j.coph.2017.12.001.CrossRefPubMedGoogle Scholar
  42. 42.
    Haas LT, Kostylev MA, Strittmatter SM. Therapeutic molecules and endogenous ligands regulate the interaction between brain cellular prion protein (PrPC) and metabotropic glutamate receptor 5 (mGluR5). J Biol Chem. 2014;289:28460–77.  https://doi.org/10.1074/jbc.M114.584342.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Hamilton A, Esseltine JL, DeVries RA, Cregan SP, Ferguson SS. Metabotropic glutamate receptor 5 knockout reduces cognitive impairment and pathogenesis in a mouse model of Alzheimer’s disease. Mol Brain. 2014;7:40.  https://doi.org/10.1186/1756-6606-7-40.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Hamilton A, Vasefi M, Vander Tuin C, McQuaid RJ, Anisman H, Ferguson SS. Chronic pharmacological mGluR5 inhibition prevents cognitive impairment and reduces pathogenesis in an Alzheimer disease mouse model. Cell Rep. 2016;15:1859–65.  https://doi.org/10.1016/j.celrep.2016.04.077.CrossRefPubMedGoogle Scholar
  45. 45.
    Haas LT, Salazar SV, Smith LM, Zhao HR, Cox TO, Herber CS, et al. Silent allosteric modulation of mGluR5 maintains glutamate signalling while rescuing Alzheimer’s mouse phenotypes. Cell Rep. 2017;20:76–88.  https://doi.org/10.1016/j.celrep.2017.06.023.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Warnock G, Sommerauer M, Mu L, Pla Gonzalez G, Geistlich S, Treyer V, et al. A first-in-man PET study of [(18)F]PSS232, a fluorinated ABP688 derivative for imaging metabotropic glutamate receptor subtype 5. Eur J Nucl Med Mol Imaging. 2018;45:1041–51.  https://doi.org/10.1007/s00259-017-3879-x.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Center for Radiopharmaceutical Sciences of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETHZurichSwitzerland
  2. 2.Neuromuscular Diseases Unit/ALS ClinicKantonsspital St. Gallen9007 St. GallenSwitzerland

Personalised recommendations