Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism
Abstract Microglia adopt numerous fates with homeostatic microglia (HM) and a microglial neurodegenerative phenotype (MGnD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Al...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2019-06-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201809711 |
| _version_ | 1797287699814547456 |
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| author | Julia K Götzl Matthias Brendel Georg Werner Samira Parhizkar Laura Sebastian Monasor Gernot Kleinberger Alessio‐Vittorio Colombo Maximilian Deussing Matias Wagner Juliane Winkelmann Janine Diehl‐Schmid Johannes Levin Katrin Fellerer Anika Reifschneider Sebastian Bultmann Peter Bartenstein Axel Rominger Sabina Tahirovic Scott T Smith Charlotte Madore Oleg Butovsky Anja Capell Christian Haass |
| author_facet | Julia K Götzl Matthias Brendel Georg Werner Samira Parhizkar Laura Sebastian Monasor Gernot Kleinberger Alessio‐Vittorio Colombo Maximilian Deussing Matias Wagner Juliane Winkelmann Janine Diehl‐Schmid Johannes Levin Katrin Fellerer Anika Reifschneider Sebastian Bultmann Peter Bartenstein Axel Rominger Sabina Tahirovic Scott T Smith Charlotte Madore Oleg Butovsky Anja Capell Christian Haass |
| author_sort | Julia K Götzl |
| collection | DOAJ |
| description | Abstract Microglia adopt numerous fates with homeostatic microglia (HM) and a microglial neurodegenerative phenotype (MGnD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Among these genes are progranulin (GRN) and the triggering receptor expressed on myeloid cells 2 (TREM2). Both cause neurodegeneration by mechanisms involving loss of function. We have now isolated microglia from Grn−/− mice and compared their transcriptomes to those of Trem2−/− mice. Surprisingly, while loss of Trem2 enhances the expression of genes associated with a homeostatic state, microglia derived from Grn−/− mice showed a reciprocal activation of the MGnD molecular signature and suppression of gene characteristic for HM. The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro‐2‐deoxy‐d‐glucose)‐μPET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction. |
| first_indexed | 2024-03-07T18:38:15Z |
| format | Article |
| id | doaj.art-47eb08eec9b445dda38fa257ed92ac93 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T18:38:15Z |
| publishDate | 2019-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-47eb08eec9b445dda38fa257ed92ac932024-03-02T04:43:29ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-06-01116n/an/a10.15252/emmm.201809711Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolismJulia K Götzl0Matthias Brendel1Georg Werner2Samira Parhizkar3Laura Sebastian Monasor4Gernot Kleinberger5Alessio‐Vittorio Colombo6Maximilian Deussing7Matias Wagner8Juliane Winkelmann9Janine Diehl‐Schmid10Johannes Levin11Katrin Fellerer12Anika Reifschneider13Sebastian Bultmann14Peter Bartenstein15Axel Rominger16Sabina Tahirovic17Scott T Smith18Charlotte Madore19Oleg Butovsky20Anja Capell21Christian Haass22Chair of Metabolic Biochemistry Biomedical Center (BMC) Faculty of Medicine Ludwig‐Maximilians‐Universität München Munich GermanyDepartment of Nuclear Medicine University Hospital Ludwig‐Maximilians‐Universität München Munich GermanyChair of Metabolic Biochemistry Biomedical Center (BMC) Faculty of Medicine Ludwig‐Maximilians‐Universität München Munich GermanyChair of Metabolic Biochemistry Biomedical Center (BMC) Faculty of Medicine Ludwig‐Maximilians‐Universität München Munich GermanyGerman Center for Neurodegenerative Diseases (DZNE) Munich GermanyChair of Metabolic Biochemistry Biomedical Center (BMC) Faculty of Medicine Ludwig‐Maximilians‐Universität München Munich GermanyGerman Center for Neurodegenerative Diseases (DZNE) Munich GermanyDepartment of Nuclear Medicine University Hospital Ludwig‐Maximilians‐Universität München Munich GermanyInstitut für Neurogenomik Helmholtz Zentrum München Munich GermanyInstitut für Neurogenomik Helmholtz Zentrum München Munich GermanyDepartment of Psychiatry Technische Universität München Munich GermanyGerman Center for Neurodegenerative Diseases (DZNE) Munich GermanyChair of Metabolic Biochemistry Biomedical Center (BMC) Faculty of Medicine Ludwig‐Maximilians‐Universität München Munich GermanyChair of Metabolic Biochemistry Biomedical Center (BMC) Faculty of Medicine Ludwig‐Maximilians‐Universität München Munich GermanyDepartment of Biology and Center for Integrated Protein Science Munich (CIPSM) Ludwig Maximilians‐Universität München Munich GermanyDepartment of Nuclear Medicine University Hospital Ludwig‐Maximilians‐Universität München Munich GermanyDepartment of Nuclear Medicine University Hospital Ludwig‐Maximilians‐Universität München Munich GermanyGerman Center for Neurodegenerative Diseases (DZNE) Munich GermanyAnn Romney Center for Neurologic Diseases Department of Neurology Brigham and Women′s Hospital Harvard Medical School Boston MA USAAnn Romney Center for Neurologic Diseases Department of Neurology Brigham and Women′s Hospital Harvard Medical School Boston MA USAAnn Romney Center for Neurologic Diseases Department of Neurology Brigham and Women′s Hospital Harvard Medical School Boston MA USAChair of Metabolic Biochemistry Biomedical Center (BMC) Faculty of Medicine Ludwig‐Maximilians‐Universität München Munich GermanyChair of Metabolic Biochemistry Biomedical Center (BMC) Faculty of Medicine Ludwig‐Maximilians‐Universität München Munich GermanyAbstract Microglia adopt numerous fates with homeostatic microglia (HM) and a microglial neurodegenerative phenotype (MGnD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Among these genes are progranulin (GRN) and the triggering receptor expressed on myeloid cells 2 (TREM2). Both cause neurodegeneration by mechanisms involving loss of function. We have now isolated microglia from Grn−/− mice and compared their transcriptomes to those of Trem2−/− mice. Surprisingly, while loss of Trem2 enhances the expression of genes associated with a homeostatic state, microglia derived from Grn−/− mice showed a reciprocal activation of the MGnD molecular signature and suppression of gene characteristic for HM. The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro‐2‐deoxy‐d‐glucose)‐μPET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction.https://doi.org/10.15252/emmm.201809711disease‐associated and homeostatic microglial signaturesmicroglianeurodegenerationprogranulinTREM2 |
| spellingShingle | Julia K Götzl Matthias Brendel Georg Werner Samira Parhizkar Laura Sebastian Monasor Gernot Kleinberger Alessio‐Vittorio Colombo Maximilian Deussing Matias Wagner Juliane Winkelmann Janine Diehl‐Schmid Johannes Levin Katrin Fellerer Anika Reifschneider Sebastian Bultmann Peter Bartenstein Axel Rominger Sabina Tahirovic Scott T Smith Charlotte Madore Oleg Butovsky Anja Capell Christian Haass Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism EMBO Molecular Medicine disease‐associated and homeostatic microglial signatures microglia neurodegeneration progranulin TREM2 |
| title | Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism |
| title_full | Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism |
| title_fullStr | Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism |
| title_full_unstemmed | Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism |
| title_short | Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism |
| title_sort | opposite microglial activation stages upon loss of pgrn or trem2 result in reduced cerebral glucose metabolism |
| topic | disease‐associated and homeostatic microglial signatures microglia neurodegeneration progranulin TREM2 |
| url | https://doi.org/10.15252/emmm.201809711 |
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