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

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

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.

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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.

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Authors and Affiliations

  1. Center for Radiopharmaceutical Sciences of ETH, PSI, and USZ, Department of Chemistry and Applied Biosciences of ETH, 8093, Zurich, Switzerland

    Adrienne Müller Herde, Roger Schibli & Simon M. Ametamey

  2. Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland

    Markus Weber

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  1. Adrienne Müller Herde
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Correspondence to Simon M. Ametamey.

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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.

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Müller Herde, A., Schibli, R., Weber, M. et al. Metabotropic glutamate receptor subtype 5 is altered in LPS-induced murine neuroinflammation model and in the brains of AD and ALS patients. Eur J Nucl Med Mol Imaging 46, 407–420 (2019). https://doi.org/10.1007/s00259-018-4179-9

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