Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease
Abstract Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between tho...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-01-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-020-01099-x |
| _version_ | 1818936743472136192 |
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| author | Akira Sobue Okiru Komine Yuichiro Hara Fumito Endo Hiroyuki Mizoguchi Seiji Watanabe Shigeo Murayama Takashi Saito Takaomi C. Saido Naruhiko Sahara Makoto Higuchi Tomoo Ogi Koji Yamanaka |
| author_facet | Akira Sobue Okiru Komine Yuichiro Hara Fumito Endo Hiroyuki Mizoguchi Seiji Watanabe Shigeo Murayama Takashi Saito Takaomi C. Saido Naruhiko Sahara Makoto Higuchi Tomoo Ogi Koji Yamanaka |
| author_sort | Akira Sobue |
| collection | DOAJ |
| description | Abstract Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, App NL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer’s change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human. |
| first_indexed | 2024-12-20T05:40:55Z |
| format | Article |
| id | doaj.art-f0f701e9e83d46abbb0f133d94d230a5 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-20T05:40:55Z |
| publishDate | 2021-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-f0f701e9e83d46abbb0f133d94d230a52022-12-21T19:51:27ZengBMCActa Neuropathologica Communications2051-59602021-01-019111710.1186/s40478-020-01099-xMicroglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s diseaseAkira Sobue0Okiru Komine1Yuichiro Hara2Fumito Endo3Hiroyuki Mizoguchi4Seiji Watanabe5Shigeo Murayama6Takashi Saito7Takaomi C. Saido8Naruhiko Sahara9Makoto Higuchi10Tomoo Ogi11Koji Yamanaka12Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya UniversityDepartment of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya UniversityDepartment of Genetics, Research Institute of Environmental Medicine, Nagoya UniversityDepartment of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya UniversityResearch Center for Next-Generation Drug Development, Research Institute of Environmental Medicine, Nagoya UniversityDepartment of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya UniversityBrain Bank for Aging Research, Tokyo Metropolitan Geriatric Hospital and Institute of GerontologyDepartment of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya UniversityLaboratory for Proteolytic Neuroscience, RIKEN Center for Brain ScienceDepartment of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and TechnologyDepartment of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and TechnologyDepartment of Genetics, Research Institute of Environmental Medicine, Nagoya UniversityDepartment of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya UniversityAbstract Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, App NL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer’s change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.https://doi.org/10.1186/s40478-020-01099-xAlzheimer’s diseaseAnimal modelNext generation sequenceMicrogliaPrecuneusNeuroinflammation |
| spellingShingle | Akira Sobue Okiru Komine Yuichiro Hara Fumito Endo Hiroyuki Mizoguchi Seiji Watanabe Shigeo Murayama Takashi Saito Takaomi C. Saido Naruhiko Sahara Makoto Higuchi Tomoo Ogi Koji Yamanaka Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease Acta Neuropathologica Communications Alzheimer’s disease Animal model Next generation sequence Microglia Precuneus Neuroinflammation |
| title | Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease |
| title_full | Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease |
| title_fullStr | Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease |
| title_full_unstemmed | Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease |
| title_short | Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease |
| title_sort | microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of alzheimer s disease |
| topic | Alzheimer’s disease Animal model Next generation sequence Microglia Precuneus Neuroinflammation |
| url | https://doi.org/10.1186/s40478-020-01099-x |
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