Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases
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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Science::Medicine Experimental Autoimmune Encephalomyelitis Alzheimers-disease |
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Science::Medicine Experimental Autoimmune Encephalomyelitis Alzheimers-disease Nutma, Erik Fancy, Nurun Weinert, Maria Tsartsalis, Stergios Marzin, Manuel C. Muirhead, Robert C. J. Falk, Irene Breur, Marjolein de Bruin, Joy Hollaus, David Pieterman, Robin Anink, Jasper Story, David Chandran, Siddharthan Tang, Jiabin Trolese, Maria C. Saito, Takashi Saido, Takaomi C. Wiltshire, Katharine H. Beltran-Lobo, Paula Phillips, Alexandra Antel, Jack Healy, Luke Dorion, Marie-France Galloway, Dylan A. Benoit, Rochelle Y. Amossé, Quentin Ceyzériat, Kelly Badina, Aurélien M. Kövari, Enikö Bendotti, Caterina Aronica, Eleonora Radulescu, Carola I. Wong, Jia Hui Barron, Anna M. Smith, Amy M. Barnes, Samuel J. Hampton, David W. van der Valk, Paul Jacobson, Steven Howell, Owain W. Baker, David Kipp, Markus Kaddatz, Hannes Tournier, Benjamin B. Millet, Philippe Matthews, Paul M. Moore, Craig S. Amor, Sandra Owen, David R. Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases |
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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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Lee Kong Chian School of Medicine (LKCMedicine) |
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Lee Kong Chian School of Medicine (LKCMedicine) Nutma, Erik Fancy, Nurun Weinert, Maria Tsartsalis, Stergios Marzin, Manuel C. Muirhead, Robert C. J. Falk, Irene Breur, Marjolein de Bruin, Joy Hollaus, David Pieterman, Robin Anink, Jasper Story, David Chandran, Siddharthan Tang, Jiabin Trolese, Maria C. Saito, Takashi Saido, Takaomi C. Wiltshire, Katharine H. Beltran-Lobo, Paula Phillips, Alexandra Antel, Jack Healy, Luke Dorion, Marie-France Galloway, Dylan A. Benoit, Rochelle Y. Amossé, Quentin Ceyzériat, Kelly Badina, Aurélien M. Kövari, Enikö Bendotti, Caterina Aronica, Eleonora Radulescu, Carola I. Wong, Jia Hui Barron, Anna M. Smith, Amy M. Barnes, Samuel J. Hampton, David W. van der Valk, Paul Jacobson, Steven Howell, Owain W. Baker, David Kipp, Markus Kaddatz, Hannes Tournier, Benjamin B. Millet, Philippe Matthews, Paul M. Moore, Craig S. Amor, Sandra Owen, David R. |
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Nutma, Erik Fancy, Nurun Weinert, Maria Tsartsalis, Stergios Marzin, Manuel C. Muirhead, Robert C. J. Falk, Irene Breur, Marjolein de Bruin, Joy Hollaus, David Pieterman, Robin Anink, Jasper Story, David Chandran, Siddharthan Tang, Jiabin Trolese, Maria C. Saito, Takashi Saido, Takaomi C. Wiltshire, Katharine H. Beltran-Lobo, Paula Phillips, Alexandra Antel, Jack Healy, Luke Dorion, Marie-France Galloway, Dylan A. Benoit, Rochelle Y. Amossé, Quentin Ceyzériat, Kelly Badina, Aurélien M. Kövari, Enikö Bendotti, Caterina Aronica, Eleonora Radulescu, Carola I. Wong, Jia Hui Barron, Anna M. Smith, Amy M. Barnes, Samuel J. Hampton, David W. van der Valk, Paul Jacobson, Steven Howell, Owain W. Baker, David Kipp, Markus Kaddatz, Hannes Tournier, Benjamin B. Millet, Philippe Matthews, Paul M. Moore, Craig S. Amor, Sandra Owen, David R. |
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Nutma, Erik |
title |
Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases |
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 |
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2023 |
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https://hdl.handle.net/10356/171517 |
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1781793885064790016 |
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sg-ntu-dr.10356-1715172023-10-29T15:38:07Z Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases Nutma, Erik Fancy, Nurun Weinert, Maria Tsartsalis, Stergios Marzin, Manuel C. Muirhead, Robert C. J. Falk, Irene Breur, Marjolein de Bruin, Joy Hollaus, David Pieterman, Robin Anink, Jasper Story, David Chandran, Siddharthan Tang, Jiabin Trolese, Maria C. Saito, Takashi Saido, Takaomi C. Wiltshire, Katharine H. Beltran-Lobo, Paula Phillips, Alexandra Antel, Jack Healy, Luke Dorion, Marie-France Galloway, Dylan A. Benoit, Rochelle Y. Amossé, Quentin Ceyzériat, Kelly Badina, Aurélien M. Kövari, Enikö Bendotti, Caterina Aronica, Eleonora Radulescu, Carola I. Wong, Jia Hui Barron, Anna M. Smith, Amy M. Barnes, Samuel J. Hampton, David W. van der Valk, Paul Jacobson, Steven Howell, Owain W. Baker, David Kipp, Markus Kaddatz, Hannes Tournier, Benjamin B. Millet, Philippe Matthews, Paul M. Moore, Craig S. Amor, Sandra Owen, David R. Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Experimental Autoimmune Encephalomyelitis Alzheimers-disease 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 version 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”). 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. 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). 2023-10-27T07:07:59Z 2023-10-27T07:07:59Z 2023 Journal Article Nutma, E., Fancy, N., Weinert, M., Tsartsalis, S., Marzin, M. C., Muirhead, R. C. J., Falk, I., Breur, M., de Bruin, J., Hollaus, D., Pieterman, R., Anink, J., Story, D., Chandran, S., Tang, J., Trolese, M. C., Saito, T., Saido, T. C., Wiltshire, K. H., ...Owen, D. R. (2023). Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases. Nature Communications, 14, 5247-. https://dx.doi.org/10.1038/s41467-023-40937-z 2041-1723 https://hdl.handle.net/10356/171517 10.1038/s41467-023-40937-z 37640701 2-s2.0-85168883392 14 5247 en Nature Communications © 2023 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. application/pdf |