Beyond Quiescent and Active: Intermediate Microglial Transcriptomic States in a Mouse Model of Down Syndrome
Research on microglia in Down syndrome (DS) has shown that microglial activation, increased inflammatory gene expression, and oxidative stress occur at different ages in DS brains. However, most studies resulted in simplistic definitions of microglia as quiescent or active, ignoring potential interm...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/6/3289 |
| _version_ | 1797240720991453184 |
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| author | Álvaro Fernández-Blanco Cèsar Sierra Clara Tejido Mara Dierssen |
| author_facet | Álvaro Fernández-Blanco Cèsar Sierra Clara Tejido Mara Dierssen |
| author_sort | Álvaro Fernández-Blanco |
| collection | DOAJ |
| description | Research on microglia in Down syndrome (DS) has shown that microglial activation, increased inflammatory gene expression, and oxidative stress occur at different ages in DS brains. However, most studies resulted in simplistic definitions of microglia as quiescent or active, ignoring potential intermediate states. Indeed, recent work on microglial cells in young DS brains indicated that those evolve through different intermediate activation phenotypes before reaching a fully activated state. Here we used single nucleus RNA sequencing, to examine how trisomy affects microglial states in the Ts65Dn mouse model of DS. Despite no substantial changes in the proportion of glial populations, differential expression analysis revealed cell type-specific gene expression changes, most notably in astroglia, microglia, and oligodendroglia. Focusing on microglia, we identified differential expression of genes associated with different microglial states, including disease-associated microglia (DAMs), activated response microglia (ARMs), and human Alzheimer’s disease microglia (HAMs), in trisomic microglia. Furthermore, pseudotime analysis reveals a unique reactivity profile in Ts65Dn microglia, with fewer in a homeostatic state and more in an intermediate aberrantly reactive state than in euploid microglia. This comprehensive understanding of microglial transcriptional dynamics sheds light on potential pathogenetic mechanisms but also possible avenues for therapy for neurodevelopmental disorders. |
| first_indexed | 2024-04-24T18:11:55Z |
| format | Article |
| id | doaj.art-f2bad98ed2b84cab8631db892c9af198 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-24T18:11:55Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f2bad98ed2b84cab8631db892c9af1982024-03-27T13:45:36ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01256328910.3390/ijms25063289Beyond Quiescent and Active: Intermediate Microglial Transcriptomic States in a Mouse Model of Down SyndromeÁlvaro Fernández-Blanco0Cèsar Sierra1Clara Tejido2Mara Dierssen3Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003 Barcelona, SpainLaboratory of Neuroepigenetics, Brain Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, SwitzerlandNeuroimmunology and Brain Tumor Immunology (D170), German Cancer Research Center, 69120 Heidelberg, GermanyCentre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003 Barcelona, SpainResearch on microglia in Down syndrome (DS) has shown that microglial activation, increased inflammatory gene expression, and oxidative stress occur at different ages in DS brains. However, most studies resulted in simplistic definitions of microglia as quiescent or active, ignoring potential intermediate states. Indeed, recent work on microglial cells in young DS brains indicated that those evolve through different intermediate activation phenotypes before reaching a fully activated state. Here we used single nucleus RNA sequencing, to examine how trisomy affects microglial states in the Ts65Dn mouse model of DS. Despite no substantial changes in the proportion of glial populations, differential expression analysis revealed cell type-specific gene expression changes, most notably in astroglia, microglia, and oligodendroglia. Focusing on microglia, we identified differential expression of genes associated with different microglial states, including disease-associated microglia (DAMs), activated response microglia (ARMs), and human Alzheimer’s disease microglia (HAMs), in trisomic microglia. Furthermore, pseudotime analysis reveals a unique reactivity profile in Ts65Dn microglia, with fewer in a homeostatic state and more in an intermediate aberrantly reactive state than in euploid microglia. This comprehensive understanding of microglial transcriptional dynamics sheds light on potential pathogenetic mechanisms but also possible avenues for therapy for neurodevelopmental disorders.https://www.mdpi.com/1422-0067/25/6/3289Down syndromemicrogliadisease-associated microglia |
| spellingShingle | Álvaro Fernández-Blanco Cèsar Sierra Clara Tejido Mara Dierssen Beyond Quiescent and Active: Intermediate Microglial Transcriptomic States in a Mouse Model of Down Syndrome International Journal of Molecular Sciences Down syndrome microglia disease-associated microglia |
| title | Beyond Quiescent and Active: Intermediate Microglial Transcriptomic States in a Mouse Model of Down Syndrome |
| title_full | Beyond Quiescent and Active: Intermediate Microglial Transcriptomic States in a Mouse Model of Down Syndrome |
| title_fullStr | Beyond Quiescent and Active: Intermediate Microglial Transcriptomic States in a Mouse Model of Down Syndrome |
| title_full_unstemmed | Beyond Quiescent and Active: Intermediate Microglial Transcriptomic States in a Mouse Model of Down Syndrome |
| title_short | Beyond Quiescent and Active: Intermediate Microglial Transcriptomic States in a Mouse Model of Down Syndrome |
| title_sort | beyond quiescent and active intermediate microglial transcriptomic states in a mouse model of down syndrome |
| topic | Down syndrome microglia disease-associated microglia |
| url | https://www.mdpi.com/1422-0067/25/6/3289 |
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