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Histone Deacetylases 1 and 2 Regulate Microglia Function during Development, Homeostasis, and Neurodegeneration in a Context-Dependent Manner
Open accessAbstract
Microglia as tissue macrophages contribute to the defense and maintenance of central nervous system (CNS) homeostasis. Little is known about the epigenetic signals controlling microglia function in vivo. We employed constitutive and inducible mutagenesis in microglia to delete two class I histone deacetylases, Hdac1 and Hdac2. Prenatal ablation of Hdac1 and Hdac2 impaired microglial development. Mechanistically, the promoters of pro-apoptotic and cell cycle genes were hyperacetylated in absence of Hdac1 and Hdac2, leading to increased apoptosis and reduced survival. In contrast, Hdac1 and Hdac2 were not required for adult microglia survival during homeostasis. In a mouse model of Alzheimer's disease, deletion of Hdac1 and Hdac2 in microglia, but not in neuroectodermal cells, resulted in a decrease in amyloid load and improved cognitive impairment by enhancing microglial amyloid phagocytosis. Collectively, we report a role for epigenetic factors that differentially affect microglia development, homeostasis, and disease that could potentially be utilized therapeutically.
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“This is exemplified by the notable findings that the genetic deletion of microglial Hdac1 and Hdac2 substantially ameliorated the cognitive deficits of 5xFAD mice by enhancing microglial phagocytosis of Aβ.298”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [298]
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Metadata
- Authors
- Datta, M., Staszewski, O., Raschi, E., Frosch, M., Hagemeyer, N., Tay, T. L., Blank, T., Kreutzfeldt, M., Merkler, D., Ziegler-Waldkirch, S., Matthias, P., Meyer-Luehmann, M., & Prinz, M.
- Affiliations
- University of Freiburg (DE)
- University of Bologna (IT)
- University of Geneva (CH)
- Friedrich Miescher Institute (CH)
- Corresponding author
- Datta, Moumita
- Prinz, Marco
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 48
- Issue
- 3
- Pages
- 514-529.e6
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2789949980
- Cited by
- 206
- References
- 55
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 32 · 2023: 21 · 2022: 14 · 2021: 29 · 2020: 34 · 2019: 24 · 2018: 16
- FWCI
- 11.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- BMBF-funded competence network of multiple sclerosis (KKNMS) (01GI1303B)
- Sobek-Foundation
- DFG (SFB 992, SFB1160, SFB/TRR167)
- Ministry of Science, Research and Arts, Baden-Wuerttemberg
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- microglia, histone deacetylase, HDAC1, HDAC2, epigenetic regulation, microglial development, microglial homeostasis, neurodegeneration, Alzheimer's disease, microglial apoptosis, cognitive impairment, CNS homeostasis
- MeSH terms
- Animals, Disease Models, Animal, Gene Expression Regulation, Histones, Homeostasis, Memory Disorders, Mice, Transgenic, Phagocytosis, Gene Expression, Apoptosis, Microglia, Mice, Knockout, Neurodegenerative Diseases, Gene Expression Profiling, Epigenesis, Genetic, Cell Proliferation, Mice, Neurogenesis, Histone Deacetylase 1, Histone Deacetylase 2, Plaque, Amyloid, Transcriptome, Spatial Learning
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