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Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases
Erik Nutma 
,
Nurun Fancy ,
Maria Weinert ,
Stergios Tsartsalis ,
Manuel C. Marzin,
Robert C. J. Muirhead,
Irene Falk,
Marjolein Breur,
Joy de Bruin,
David Hollaus,
Robin Pieterman,
Jasper Anink,
David Story,
Siddharthan Chandran,
Jiabin Tang,
Maria C. Trolese ,
Takashi Saito ,
Takaomi C. Saido,
Katharine H. Wiltshire,
Paula Beltran-Lobo,
Alexandra Phillips,
Jack Antel ,
Luke Healy ,
Marie-France Dorion,
Dylan A. Galloway,
Rochelle Y. Benoit,
Quentin Amossé ,
Kelly Ceyzériat,
Aurélien M. Badina ,
Enikö Kövari,
Caterina Bendotti ,
Eleonora Aronica ,
Carola I. Radulescu,
Jia Hui Wong ,
Anna M. Barron ,
Amy M. Smith,
Samuel J. Barnes ,
David W. Hampton,
Paul van der Valk,
Steven Jacobson,
Owain Howell ,
David Baker,
Markus Kipp ,
Hannes Kaddatz ,
Benjamin B. Tournier ,
Philippe Millet ,
Paul M. Matthews ,
Craig S. Moore ,
Sandra Amor,
David R. Owen
,
Nurun Fancy ,
Maria Weinert ,
Stergios Tsartsalis ,
Manuel C. Marzin,
Robert C. J. Muirhead,
Irene Falk,
Marjolein Breur,
Joy de Bruin,
David Hollaus,
Robin Pieterman,
Jasper Anink,
David Story,
Siddharthan Chandran,
Jiabin Tang,
Maria C. Trolese ,
Takashi Saito ,
Takaomi C. Saido,
Katharine H. Wiltshire,
Paula Beltran-Lobo,
Alexandra Phillips,
Jack Antel ,
Luke Healy ,
Marie-France Dorion,
Dylan A. Galloway,
Rochelle Y. Benoit,
Quentin Amossé ,
Kelly Ceyzériat,
Aurélien M. Badina ,
Enikö Kövari,
Caterina Bendotti ,
Eleonora Aronica ,
Carola I. Radulescu,
Jia Hui Wong ,
Anna M. Barron ,
Amy M. Smith,
Samuel J. Barnes ,
David W. Hampton,
Paul van der Valk,
Steven Jacobson,
Owain Howell ,
David Baker,
Markus Kipp ,
Hannes Kaddatz ,
Benjamin B. Tournier ,
Philippe Millet ,
Paul M. Matthews ,
Craig S. Moore ,
Sandra Amor,
David R. Owen
Nature Communications, Volume: 14, Issue: 1
Swansea University Author:
Owain Howell
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© The Author(s) 2023. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0).
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DOI (Published version): 10.1038/s41467-023-40937-z
Abstract
Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO...
| Published in: | Nature Communications |
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| ISSN: | 2041-1723 |
| Published: |
Springer Science and Business Media LLC
2023
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa64510 |
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| Abstract: |
Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state. |
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| Keywords: |
Translocator protein, TSPO, positron emission tomography, PET, neurodegenerative diseases, neuroinflammatory diseases, microglial activation |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
The authors thank the UK MS Society for financial support (grant number: C008-16.1). DRO was funded by an MRC Clinician Scientist Award (MR/N008219/1). P.M.M. acknowledges generous support from Edmond J Safra Foundation and Lily Safra, the NIHR Senior Investigator programme and the UK Dementia Research Institute which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK. P.M.M. and D.R.O. thank the Imperial College Healthcare Trust-NIHR Biomedical Research Centre for infrastructure support and the Medical Research Council for support of TSPO studies (MR/N016343/1). E.A. was supported by the ALS Stichting (grant “The Dutch ALS Tissue Bank”). Dr. Sally Cowley (Oxford Parkinson’s Disease Centre, James Martin Stem Cell Facility, University of Oxford) provided the iPS cell line and expertise in differentiation to iPS-microglia. All authors thank the NIHR Imperial Clinical Research Facility (ICRF) for supporting procedures relating to collection of blood samples. P.M. and B.B.T. are funded by the Swiss National Science Foundation (projects 320030_184713 and 310030_212322, respectively). S.T. was supported by an “Early Postdoc.Mobility” scholarship (P2GEP3_191446) from the Swiss National Science Foundation, a “Clinical Medicine Plus” scholarship from the Prof Dr. Max Cloëtta Foundation (Zurich, Switzerland), from the Jean et Madeleine Vachoux Foundation (Geneva, Switzerland) and from the University Hospitals of Geneva. The authors wish to thank Pia Lovero and Adrien Fischer for expert technical assistance. The results published here are in part based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.org). Study data were generated from postmortem brain tissue provided by the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) cohort at Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. This work was funded by NIH grants U01AG061356 (De Jager/Bennett), RF1AG057473 (De Jager/Bennett), and U01AG046152 (De Jager/Bennett) as part of the AMP-AD consortium, as well as NIH grants R01AG066831 (Menon) and U01AG072572 (De Jager/St George-Hyslop). |
| Issue: |
1 |