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Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases

Erik Nutma Orcid Logo, Nurun Fancy Orcid Logo, Maria Weinert Orcid Logo, Stergios Tsartsalis Orcid Logo, 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 Orcid Logo, Takashi Saito Orcid Logo, Takaomi C. Saido, Katharine H. Wiltshire, Paula Beltran-Lobo, Alexandra Phillips, Jack Antel Orcid Logo, Luke Healy Orcid Logo, Marie-France Dorion, Dylan A. Galloway, Rochelle Y. Benoit, Quentin Amossé Orcid Logo, Kelly Ceyzériat, Aurélien M. Badina Orcid Logo, Enikö Kövari, Caterina Bendotti Orcid Logo, Eleonora Aronica Orcid Logo, Carola I. Radulescu, Jia Hui Wong Orcid Logo, Anna M. Barron Orcid Logo, Amy M. Smith, Samuel J. Barnes Orcid Logo, David W. Hampton, Paul van der Valk, Steven Jacobson, Owain Howell Orcid Logo, David Baker, Markus Kipp Orcid Logo, Hannes Kaddatz Orcid Logo, Benjamin B. Tournier Orcid Logo, Philippe Millet Orcid Logo, Paul M. Matthews Orcid Logo, Craig S. Moore Orcid Logo, Sandra Amor, David R. Owen Orcid Logo

Nature Communications, Volume: 14, Issue: 1

Swansea University Author: Owain Howell Orcid Logo

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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...

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Published in: Nature Communications
ISSN: 2041-1723
Published: Springer Science and Business Media LLC 2023
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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. 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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&#x2019;s Society, and Alzheimer&#x2019;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 &#x201C;The Dutch ALS Tissue Bank&#x201D;). Dr. Sally Cowley (Oxford Parkinson&#x2019;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 &#x201C;Early Postdoc.Mobility&#x201D; scholarship (P2GEP3_191446) from the Swiss National Science Foundation, a &#x201C;Clinical Medicine Plus&#x201D; scholarship from the Prof Dr. Max Clo&#xEB;tta 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&#x2019;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).</funders><projectreference/><lastEdited>2024-02-01T16:05:12.8644746</lastEdited><Created>2023-09-12T09:33:22.8297880</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Erik</firstname><surname>Nutma</surname><orcid>0000-0002-7332-1636</orcid><order>1</order></author><author><firstname>Nurun</firstname><surname>Fancy</surname><orcid>0000-0002-6481-6266</orcid><order>2</order></author><author><firstname>Maria</firstname><surname>Weinert</surname><orcid>0000-0001-6187-1000</orcid><order>3</order></author><author><firstname>Stergios</firstname><surname>Tsartsalis</surname><orcid>0000-0002-6565-6313</orcid><order>4</order></author><author><firstname>Manuel C.</firstname><surname>Marzin</surname><order>5</order></author><author><firstname>Robert C. 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spelling 2024-02-01T16:05:12.8644746 v2 64510 2023-09-12 Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases 58c995486fc93a242b987640b692db8c 0000-0003-2157-9157 Owain Howell Owain Howell true false 2023-09-12 MEDS 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. Journal Article Nature Communications 14 1 Springer Science and Business Media LLC 2041-1723 Translocator protein, TSPO, positron emission tomography, PET, neurodegenerative diseases, neuroinflammatory diseases, microglial activation 28 8 2023 2023-08-28 10.1038/s41467-023-40937-z http://dx.doi.org/10.1038/s41467-023-40937-z COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University 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). 2024-02-01T16:05:12.8644746 2023-09-12T09:33:22.8297880 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Erik Nutma 0000-0002-7332-1636 1 Nurun Fancy 0000-0002-6481-6266 2 Maria Weinert 0000-0001-6187-1000 3 Stergios Tsartsalis 0000-0002-6565-6313 4 Manuel C. Marzin 5 Robert C. J. Muirhead 6 Irene Falk 7 Marjolein Breur 8 Joy de Bruin 9 David Hollaus 10 Robin Pieterman 11 Jasper Anink 12 David Story 13 Siddharthan Chandran 14 Jiabin Tang 15 Maria C. Trolese 0000-0003-4471-2491 16 Takashi Saito 0000-0002-9659-9251 17 Takaomi C. Saido 18 Katharine H. Wiltshire 19 Paula Beltran-Lobo 20 Alexandra Phillips 21 Jack Antel 0000-0002-5148-0636 22 Luke Healy 0000-0001-9496-2216 23 Marie-France Dorion 24 Dylan A. Galloway 25 Rochelle Y. Benoit 26 Quentin Amossé 0000-0002-5553-9594 27 Kelly Ceyzériat 28 Aurélien M. Badina 0009-0005-1890-8986 29 Enikö Kövari 30 Caterina Bendotti 0000-0003-1055-1271 31 Eleonora Aronica 0000-0002-3542-3770 32 Carola I. Radulescu 33 Jia Hui Wong 0000-0002-7036-8121 34 Anna M. Barron 0000-0002-4715-9364 35 Amy M. Smith 36 Samuel J. Barnes 0000-0003-4030-6453 37 David W. Hampton 38 Paul van der Valk 39 Steven Jacobson 40 Owain Howell 0000-0003-2157-9157 41 David Baker 42 Markus Kipp 0000-0001-5043-9052 43 Hannes Kaddatz 0000-0003-1927-7344 44 Benjamin B. Tournier 0000-0002-8027-7530 45 Philippe Millet 0000-0002-5803-0478 46 Paul M. Matthews 0000-0002-1619-8328 47 Craig S. Moore 0000-0003-3333-435x 48 Sandra Amor 49 David R. Owen 0000-0002-1198-7563 50 64510__28701__5fe55ad798f743b487bef368d4ae4064.pdf 64510.VOR.pdf 2023-10-04T14:07:01.6853171 Output 9031134 application/pdf Version of Record true © The Author(s) 2023. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases
spellingShingle Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases
Owain Howell
title_short Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases
title_full Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases
title_fullStr Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases
title_full_unstemmed Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases
title_sort Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases
author_id_str_mv 58c995486fc93a242b987640b692db8c
author_id_fullname_str_mv 58c995486fc93a242b987640b692db8c_***_Owain Howell
author Owain Howell
author2 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
format Journal article
container_title Nature Communications
container_volume 14
container_issue 1
publishDate 2023
institution Swansea University
issn 2041-1723
doi_str_mv 10.1038/s41467-023-40937-z
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
url http://dx.doi.org/10.1038/s41467-023-40937-z
document_store_str 1
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description 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.
published_date 2023-08-28T02:54:45Z
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