Metabotropic glutamate receptor subtype 5 is altered in LPS-induced murine neuroinflammation model and in the brains of AD and ALS patients
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.
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.
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.
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.
KeywordsMetabotropic glutamate receptor subtype 5 [18F]PSS232 Positron emission tomography Neuroinflammation Neurodegenerative disease Lipopolysaccharide
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
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.
- 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
- 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
- 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
- 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.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.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
- 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
- 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.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.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
- 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
- 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
- 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
- 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
- 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