Neuroinflammatory astrocyte subtypes in the mouse brain
Abstract
Astrocytes undergo an inflammatory transition after infections, acute injuries and chronic neurodegenerative diseases. How this transition is affected by time and sex, its heterogeneity at the single-cell level and how sub-states are spatially distributed in the brain remains unclear. In this study, we investigated transcriptome changes of mouse cortical astrocytes after an acute inflammatory stimulus using the bacterial cell wall endotoxin lipopolysaccharide. We identified fast transcriptomic changes in astrocytes occurring within hours that drastically change over time. By sequencing ~80,000 astrocytes at single-cell resolution, we show that inflammation causes a widespread response with subtypes of astrocytes undergoing distinct inflammatory transitions with defined transcriptomic profiles. We also attribute key sub-states of inflammation-induced reactive astrocytes to specific brain regions using spatial transcriptomics and in situ hybridization. Together, our datasets provide a powerful resource for profiling astrocyte heterogeneity and will be useful for understanding the biological importance of regionally constrained reactive astrocyte sub-states.
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Inpp5d knockdown exacerbated the plaque-induced Cluster 26 profile, which overlaps with previously reported reactive glial substates, including DEGs from both early and late DAM profiles and previously identified IRRAs.
“Indeed, our Inpp5d knockdown exacerbated the plaque-induced Cluster 26 profile, which overlaps with previously reported reactive glial substates, including DEGs from both early and late DAM profiles,25 and our previously identified IRRAs.28”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [28]
Astrocyte clusters were scored using AddModuleScore for markers from previously published genesets of astrocyte cell states, plaque-induced genes, and AD risk genes.
“Astrocyte clusters were scored using seurat::AddModuleScore(), for markers from previously published genesets of astrocyte cell states (Zamanian et al, 2012; Hasel et al, 2021), plaque-induced genes (PIGs) (Chen et al, 2020) and AD risk genes (Bellenguez et al, 2022).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Hasel et al, 2021
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- Authors
- Hasel, P., Rose, I. V. L., Sadick, J. S., Kim, R. D., & Liddelow, S. A.
- Affiliations
- NYU Langone Health (US)
- New York University (US)
- Corresponding author
- Hasel, Philip
- Liddelow, Shane A.
- Venue
- Nature Neuroscience
- Published
- 2021-08-19
- Volume
- 24
- Issue
- 10
- Pages
- 1475-1487
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W3194004635
- Cited by
- 586
- References
- 12
- Citations by year
- 2026: 94 · 2025: 109 · 2024: 135 · 2023: 142 · 2022: 83 · 2021: 21 · 2020: 1 · 2012: 1
- FWCI
- 40.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Neurodegeneration Consortium from MD Anderson
- NSF GRFP
- NYU School of Medicine Cure Alzheimer’s Fund Anonymous Donors Blas Frangione Foundation Neurodegeneration Consortium from MD Anderson
- Anonymous DonorsCure Alzheimer’s Fund
- NYU ADRC T32Cure Alzheimer’s Fund
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- reactive astrocytes, astrocyte heterogeneity, neuroinflammation, lipopolysaccharide, acute inflammation, cortical astrocytes, astrocyte subtypes, transcriptomic changes, sex differences, super-responders, mouse brain
- MeSH terms
- Animals, Astrocytes, Brain, Cells, Cultured, Encephalitis, Female, Interferons, Lipopolysaccharides, Male, Rats, Sprague-Dawley, In Situ Hybridization, Sequence Analysis, RNA, Gene Expression Profiling, Mice, Rats, Transcriptome
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