Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases
Abstract Background In vivo assessment of neuroinflammation by 18-kDa translocator protein positron-emission-tomography (TSPO-PET) ligands receives growing interest in preclinical and clinical research of neurodegenerative disorders. Higher TSPO-PET binding as a surrogate for microglial activation i...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-12-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-020-02046-2 |
| _version_ | 1819059866535198720 |
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| author | Gloria Biechele Nicolai Franzmeier Tanja Blume Michael Ewers Jose Medina Luque Florian Eckenweber Christian Sacher Leonie Beyer Francois Ruch-Rubinstein Simon Lindner Franz-Josef Gildehaus Barbara von Ungern-Sternberg Paul Cumming Peter Bartenstein Axel Rominger Günter U. Höglinger Jochen Herms Matthias Brendel |
| author_facet | Gloria Biechele Nicolai Franzmeier Tanja Blume Michael Ewers Jose Medina Luque Florian Eckenweber Christian Sacher Leonie Beyer Francois Ruch-Rubinstein Simon Lindner Franz-Josef Gildehaus Barbara von Ungern-Sternberg Paul Cumming Peter Bartenstein Axel Rominger Günter U. Höglinger Jochen Herms Matthias Brendel |
| author_sort | Gloria Biechele |
| collection | DOAJ |
| description | Abstract Background In vivo assessment of neuroinflammation by 18-kDa translocator protein positron-emission-tomography (TSPO-PET) ligands receives growing interest in preclinical and clinical research of neurodegenerative disorders. Higher TSPO-PET binding as a surrogate for microglial activation in females has been reported for cognitively normal humans, but such effects have not yet been evaluated in rodent models of neurodegeneration and their controls. Thus, we aimed to investigate the impact of sex on microglial activation in amyloid and tau mouse models and wild-type controls. Methods TSPO-PET (18F-GE-180) data of C57Bl/6 (wild-type), App NL-G-F (β-amyloid model), and P301S (tau model) mice was assessed longitudinally between 2 and 12 months of age. The App NL-G-F group also underwent longitudinal β-amyloid-PET imaging (Aβ-PET; 18F-florbetaben). PET results were confirmed and validated by immunohistochemical investigation of microglial (Iba-1, CD68), astrocytic (GFAP), and tau (AT8) markers. Findings in cerebral cortex were compared by sex using linear mixed models for PET data and analysis of variance for immunohistochemistry. Results Wild-type mice showed an increased TSPO-PET signal over time (female +23%, male +4%), with a significant sex × age interaction (T = − 4.171, p < 0.001). The Aβ model App NL-G-F mice also showed a significant sex × age interaction (T = − 2.953, p = 0.0048), where cortical TSPO-PET values increased by 31% in female App NL-G-F mice, versus only 6% in the male mice group from 2.5 to 10 months of age. Immunohistochemistry for the microglial markers Iba-1 and CD68 confirmed the TSPO-PET findings in male and female mice aged 10 months. Aβ-PET in the same App NL-G-F mice indicated no significant sex × age interaction (T = 0.425, p = 0.673). The P301S tau model showed strong cortical increases of TSPO-PET from 2 to 8.5 months of age (female + 32%, male + 36%), without any significant sex × age interaction (T = − 0.671, p = 0.504), and no sex differences in Iba-1, CD68, or AT8 immunohistochemistry. Conclusion Female mice indicate sex-dependent microglia activation in aging and in response to amyloidosis but not in response to tau pathology. This calls for consideration of sex difference in TSPO-PET studies of microglial activation in mouse models of neurodegeneration and by extension in human studies. |
| first_indexed | 2024-12-21T14:17:54Z |
| format | Article |
| id | doaj.art-51c44b3b04a64068820ce28eb0c4ff48 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-21T14:17:54Z |
| publishDate | 2020-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-51c44b3b04a64068820ce28eb0c4ff482022-12-21T19:00:51ZengBMCJournal of Neuroinflammation1742-20942020-12-0117111010.1186/s12974-020-02046-2Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseasesGloria Biechele0Nicolai Franzmeier1Tanja Blume2Michael Ewers3Jose Medina Luque4Florian Eckenweber5Christian Sacher6Leonie Beyer7Francois Ruch-Rubinstein8Simon Lindner9Franz-Josef Gildehaus10Barbara von Ungern-Sternberg11Paul Cumming12Peter Bartenstein13Axel Rominger14Günter U. Höglinger15Jochen Herms16Matthias Brendel17Department of Nuclear Medicine, University Hospital of Munich, LMU MunichInstitute for Stroke and Dementia Research, University Hospital of Munich, LMU MunichDepartment of Nuclear Medicine, University Hospital of Munich, LMU MunichInstitute for Stroke and Dementia Research, University Hospital of Munich, LMU MunichDZNE - German Center for Neurodegenerative DiseasesDepartment of Nuclear Medicine, University Hospital of Munich, LMU MunichDepartment of Nuclear Medicine, University Hospital of Munich, LMU MunichDepartment of Nuclear Medicine, University Hospital of Munich, LMU MunichDepartment of Nuclear Medicine, University Hospital of Munich, LMU MunichDepartment of Nuclear Medicine, University Hospital of Munich, LMU MunichDepartment of Nuclear Medicine, University Hospital of Munich, LMU MunichDepartment of Nuclear Medicine, University Hospital of Munich, LMU MunichDepartment of Nuclear Medicine, Inselspital, University Hospital BernDepartment of Nuclear Medicine, University Hospital of Munich, LMU MunichDepartment of Nuclear Medicine, University Hospital of Munich, LMU MunichInstitute for Stroke and Dementia Research, University Hospital of Munich, LMU MunichInstitute for Stroke and Dementia Research, University Hospital of Munich, LMU MunichDepartment of Nuclear Medicine, University Hospital of Munich, LMU MunichAbstract Background In vivo assessment of neuroinflammation by 18-kDa translocator protein positron-emission-tomography (TSPO-PET) ligands receives growing interest in preclinical and clinical research of neurodegenerative disorders. Higher TSPO-PET binding as a surrogate for microglial activation in females has been reported for cognitively normal humans, but such effects have not yet been evaluated in rodent models of neurodegeneration and their controls. Thus, we aimed to investigate the impact of sex on microglial activation in amyloid and tau mouse models and wild-type controls. Methods TSPO-PET (18F-GE-180) data of C57Bl/6 (wild-type), App NL-G-F (β-amyloid model), and P301S (tau model) mice was assessed longitudinally between 2 and 12 months of age. The App NL-G-F group also underwent longitudinal β-amyloid-PET imaging (Aβ-PET; 18F-florbetaben). PET results were confirmed and validated by immunohistochemical investigation of microglial (Iba-1, CD68), astrocytic (GFAP), and tau (AT8) markers. Findings in cerebral cortex were compared by sex using linear mixed models for PET data and analysis of variance for immunohistochemistry. Results Wild-type mice showed an increased TSPO-PET signal over time (female +23%, male +4%), with a significant sex × age interaction (T = − 4.171, p < 0.001). The Aβ model App NL-G-F mice also showed a significant sex × age interaction (T = − 2.953, p = 0.0048), where cortical TSPO-PET values increased by 31% in female App NL-G-F mice, versus only 6% in the male mice group from 2.5 to 10 months of age. Immunohistochemistry for the microglial markers Iba-1 and CD68 confirmed the TSPO-PET findings in male and female mice aged 10 months. Aβ-PET in the same App NL-G-F mice indicated no significant sex × age interaction (T = 0.425, p = 0.673). The P301S tau model showed strong cortical increases of TSPO-PET from 2 to 8.5 months of age (female + 32%, male + 36%), without any significant sex × age interaction (T = − 0.671, p = 0.504), and no sex differences in Iba-1, CD68, or AT8 immunohistochemistry. Conclusion Female mice indicate sex-dependent microglia activation in aging and in response to amyloidosis but not in response to tau pathology. This calls for consideration of sex difference in TSPO-PET studies of microglial activation in mouse models of neurodegeneration and by extension in human studies.https://doi.org/10.1186/s12974-020-02046-2SexMicrogliaTSPOAmyloidTau |
| spellingShingle | Gloria Biechele Nicolai Franzmeier Tanja Blume Michael Ewers Jose Medina Luque Florian Eckenweber Christian Sacher Leonie Beyer Francois Ruch-Rubinstein Simon Lindner Franz-Josef Gildehaus Barbara von Ungern-Sternberg Paul Cumming Peter Bartenstein Axel Rominger Günter U. Höglinger Jochen Herms Matthias Brendel Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases Journal of Neuroinflammation Sex Microglia TSPO Amyloid Tau |
| title | Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases |
| title_full | Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases |
| title_fullStr | Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases |
| title_full_unstemmed | Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases |
| title_short | Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases |
| title_sort | glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases |
| topic | Sex Microglia TSPO Amyloid Tau |
| url | https://doi.org/10.1186/s12974-020-02046-2 |
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