Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer’s disease
Microglia play a critical role in brain homeostasis and disease progression. In neurodegenerative conditions, microglia acquire the neurodegenerative phenotype (MGnD), whose function is poorly understood. MicroRNA-155 (miR-155), enriched in immune cells, critically regulates MGnD. However, its role...
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| Veröffentlicht in: | Nature neuroscience 2023-07, Vol.26 (7), p.1196-1207 |
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| creator | Yin, Zhuoran Herron, Shawn Silveira, Sebastian Kleemann, Kilian Gauthier, Christian Mallah, Dania Cheng, Yiran Margeta, Milica A. Pitts, Kristen M. Barry, Jen-Li Subramanian, Ayshwarya Shorey, Hannah Brandao, Wesley Durao, Ana Delpech, Jean-Christophe Madore, Charlotte Jedrychowski, Mark Ajay, Amrendra K. Murugaiyan, Gopal Hersh, Samuel W. Ikezu, Seiko Ikezu, Tsuneya Butovsky, Oleg |
| description | Microglia play a critical role in brain homeostasis and disease progression. In neurodegenerative conditions, microglia acquire the neurodegenerative phenotype (MGnD), whose function is poorly understood. MicroRNA-155 (miR-155), enriched in immune cells, critically regulates MGnD. However, its role in Alzheimer’s disease (AD) pathogenesis remains unclear. Here, we report that microglial deletion of miR-155 induces a pre-MGnD activation state via interferon-γ (IFN-γ) signaling, and blocking IFN-γ signaling attenuates MGnD induction and microglial phagocytosis. Single-cell RNA-sequencing analysis of microglia from an AD mouse model identifies Stat1 and Clec2d as pre-MGnD markers. This phenotypic transition enhances amyloid plaque compaction, reduces dystrophic neurites, attenuates plaque-associated synaptic degradation and improves cognition. Our study demonstrates a miR-155-mediated regulatory mechanism of MGnD and the beneficial role of IFN-γ-responsive pre-MGnD in restricting neurodegenerative pathology and preserving cognitive function in an AD mouse model, highlighting miR-155 and IFN-γ as potential therapeutic targets for AD.
Yin et al. identify miR-155–IFN-γ signaling that regulates a protective microglial subset in a mouse model of Alzheimer’s disease. These microglia enhance plaque compaction, reduce dystrophic neurites and synaptic degradation, and improve cognition. |
| doi_str_mv | 10.1038/s41593-023-01355-y |
| format | Article |
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Yin et al. identify miR-155–IFN-γ signaling that regulates a protective microglial subset in a mouse model of Alzheimer’s disease. These microglia enhance plaque compaction, reduce dystrophic neurites and synaptic degradation, and improve cognition.</description><identifier>ISSN: 1097-6256</identifier><identifier>ISSN: 1546-1726</identifier><identifier>EISSN: 1546-1726</identifier><identifier>DOI: 10.1038/s41593-023-01355-y</identifier><identifier>PMID: 37291336</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>13/106 ; 13/2 ; 13/31 ; 13/51 ; 14/1 ; 14/19 ; 38/39 ; 45/77 ; 45/90 ; 45/91 ; 631/250/371 ; 631/378/371 ; 631/378/87 ; 64/60 ; 692/699/375/365/1283 ; 82/58 ; Alzheimer Disease - metabolism ; Alzheimer's disease ; Amyloid ; Amyloid beta-Peptides - metabolism ; Animal Genetics and Genomics ; Animals ; Axons ; Behavioral Sciences ; Biological Techniques ; Biomedical and Life Sciences ; Biomedicine ; Cognition ; Cognitive ability ; Compaction ; Degradation ; Disease Models, Animal ; Gene sequencing ; Homeostasis ; Immune system ; Interferon ; Interferon-gamma - metabolism ; Life Sciences ; Mice ; Mice, Transgenic ; Microglia ; Microglia - metabolism ; MicroRNAs - genetics ; MicroRNAs - metabolism ; miRNA ; Neurobiology ; Neurodegenerative diseases ; Neurons and Cognition ; Neurosciences ; Pathogenesis ; Phagocytosis ; Phenotypes ; Plaque, Amyloid - metabolism ; Regulatory mechanisms (biology) ; Sequence analysis ; Signal Transduction - genetics ; Stat1 protein ; Therapeutic targets ; γ-Interferon</subject><ispartof>Nature neuroscience, 2023-07, Vol.26 (7), p.1196-1207</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2023. 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The Author(s), under exclusive licence to Springer Nature America, Inc.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c465t-90eb9a95319f9ddbecbdaf01dc47547ee94908c09e861c7142bc1b9b00a76dd3</citedby><cites>FETCH-LOGICAL-c465t-90eb9a95319f9ddbecbdaf01dc47547ee94908c09e861c7142bc1b9b00a76dd3</cites><orcidid>0000-0003-2790-5726 ; 0000-0003-0186-8867 ; 0000-0002-2753-6804 ; 0000-0002-3979-8596 ; 0000-0001-7049-0883 ; 0000-0001-5589-2024 ; 0000-0002-4134-7612 ; 0000-0002-0704-6496</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41593-023-01355-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41593-023-01355-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37291336$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-04227164$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Yin, Zhuoran</creatorcontrib><creatorcontrib>Herron, Shawn</creatorcontrib><creatorcontrib>Silveira, Sebastian</creatorcontrib><creatorcontrib>Kleemann, Kilian</creatorcontrib><creatorcontrib>Gauthier, Christian</creatorcontrib><creatorcontrib>Mallah, Dania</creatorcontrib><creatorcontrib>Cheng, Yiran</creatorcontrib><creatorcontrib>Margeta, Milica A.</creatorcontrib><creatorcontrib>Pitts, Kristen M.</creatorcontrib><creatorcontrib>Barry, Jen-Li</creatorcontrib><creatorcontrib>Subramanian, Ayshwarya</creatorcontrib><creatorcontrib>Shorey, Hannah</creatorcontrib><creatorcontrib>Brandao, Wesley</creatorcontrib><creatorcontrib>Durao, Ana</creatorcontrib><creatorcontrib>Delpech, Jean-Christophe</creatorcontrib><creatorcontrib>Madore, Charlotte</creatorcontrib><creatorcontrib>Jedrychowski, Mark</creatorcontrib><creatorcontrib>Ajay, Amrendra K.</creatorcontrib><creatorcontrib>Murugaiyan, Gopal</creatorcontrib><creatorcontrib>Hersh, Samuel W.</creatorcontrib><creatorcontrib>Ikezu, Seiko</creatorcontrib><creatorcontrib>Ikezu, Tsuneya</creatorcontrib><creatorcontrib>Butovsky, Oleg</creatorcontrib><title>Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer’s disease</title><title>Nature neuroscience</title><addtitle>Nat Neurosci</addtitle><addtitle>Nat Neurosci</addtitle><description>Microglia play a critical role in brain homeostasis and disease progression. In neurodegenerative conditions, microglia acquire the neurodegenerative phenotype (MGnD), whose function is poorly understood. MicroRNA-155 (miR-155), enriched in immune cells, critically regulates MGnD. However, its role in Alzheimer’s disease (AD) pathogenesis remains unclear. Here, we report that microglial deletion of miR-155 induces a pre-MGnD activation state via interferon-γ (IFN-γ) signaling, and blocking IFN-γ signaling attenuates MGnD induction and microglial phagocytosis. Single-cell RNA-sequencing analysis of microglia from an AD mouse model identifies Stat1 and Clec2d as pre-MGnD markers. This phenotypic transition enhances amyloid plaque compaction, reduces dystrophic neurites, attenuates plaque-associated synaptic degradation and improves cognition. Our study demonstrates a miR-155-mediated regulatory mechanism of MGnD and the beneficial role of IFN-γ-responsive pre-MGnD in restricting neurodegenerative pathology and preserving cognitive function in an AD mouse model, highlighting miR-155 and IFN-γ as potential therapeutic targets for AD.
Yin et al. identify miR-155–IFN-γ signaling that regulates a protective microglial subset in a mouse model of Alzheimer’s disease. These microglia enhance plaque compaction, reduce dystrophic neurites and synaptic degradation, and improve cognition.</description><subject>13/106</subject><subject>13/2</subject><subject>13/31</subject><subject>13/51</subject><subject>14/1</subject><subject>14/19</subject><subject>38/39</subject><subject>45/77</subject><subject>45/90</subject><subject>45/91</subject><subject>631/250/371</subject><subject>631/378/371</subject><subject>631/378/87</subject><subject>64/60</subject><subject>692/699/375/365/1283</subject><subject>82/58</subject><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer's disease</subject><subject>Amyloid</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Animal Genetics and Genomics</subject><subject>Animals</subject><subject>Axons</subject><subject>Behavioral Sciences</subject><subject>Biological Techniques</subject><subject>Biomedical and Life 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Edition</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yin, Zhuoran</au><au>Herron, Shawn</au><au>Silveira, Sebastian</au><au>Kleemann, Kilian</au><au>Gauthier, Christian</au><au>Mallah, Dania</au><au>Cheng, Yiran</au><au>Margeta, Milica A.</au><au>Pitts, Kristen M.</au><au>Barry, Jen-Li</au><au>Subramanian, Ayshwarya</au><au>Shorey, Hannah</au><au>Brandao, Wesley</au><au>Durao, Ana</au><au>Delpech, Jean-Christophe</au><au>Madore, Charlotte</au><au>Jedrychowski, Mark</au><au>Ajay, Amrendra K.</au><au>Murugaiyan, Gopal</au><au>Hersh, Samuel W.</au><au>Ikezu, Seiko</au><au>Ikezu, Tsuneya</au><au>Butovsky, Oleg</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer’s disease</atitle><jtitle>Nature neuroscience</jtitle><stitle>Nat Neurosci</stitle><addtitle>Nat Neurosci</addtitle><date>2023-07-01</date><risdate>2023</risdate><volume>26</volume><issue>7</issue><spage>1196</spage><epage>1207</epage><pages>1196-1207</pages><issn>1097-6256</issn><issn>1546-1726</issn><eissn>1546-1726</eissn><abstract>Microglia play a critical role in brain homeostasis and disease progression. In neurodegenerative conditions, microglia acquire the neurodegenerative phenotype (MGnD), whose function is poorly understood. MicroRNA-155 (miR-155), enriched in immune cells, critically regulates MGnD. However, its role in Alzheimer’s disease (AD) pathogenesis remains unclear. Here, we report that microglial deletion of miR-155 induces a pre-MGnD activation state via interferon-γ (IFN-γ) signaling, and blocking IFN-γ signaling attenuates MGnD induction and microglial phagocytosis. Single-cell RNA-sequencing analysis of microglia from an AD mouse model identifies Stat1 and Clec2d as pre-MGnD markers. This phenotypic transition enhances amyloid plaque compaction, reduces dystrophic neurites, attenuates plaque-associated synaptic degradation and improves cognition. Our study demonstrates a miR-155-mediated regulatory mechanism of MGnD and the beneficial role of IFN-γ-responsive pre-MGnD in restricting neurodegenerative pathology and preserving cognitive function in an AD mouse model, highlighting miR-155 and IFN-γ as potential therapeutic targets for AD.
Yin et al. identify miR-155–IFN-γ signaling that regulates a protective microglial subset in a mouse model of Alzheimer’s disease. These microglia enhance plaque compaction, reduce dystrophic neurites and synaptic degradation, and improve cognition.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>37291336</pmid><doi>10.1038/s41593-023-01355-y</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-2790-5726</orcidid><orcidid>https://orcid.org/0000-0003-0186-8867</orcidid><orcidid>https://orcid.org/0000-0002-2753-6804</orcidid><orcidid>https://orcid.org/0000-0002-3979-8596</orcidid><orcidid>https://orcid.org/0000-0001-7049-0883</orcidid><orcidid>https://orcid.org/0000-0001-5589-2024</orcidid><orcidid>https://orcid.org/0000-0002-4134-7612</orcidid><orcidid>https://orcid.org/0000-0002-0704-6496</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1097-6256 |
| ispartof | Nature neuroscience, 2023-07, Vol.26 (7), p.1196-1207 |
| issn | 1097-6256 1546-1726 1546-1726 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10619638 |
| source | MEDLINE; SpringerLink Journals; Nature Journals Online |
| subjects | 13/106 13/2 13/31 13/51 14/1 14/19 38/39 45/77 45/90 45/91 631/250/371 631/378/371 631/378/87 64/60 692/699/375/365/1283 82/58 Alzheimer Disease - metabolism Alzheimer's disease Amyloid Amyloid beta-Peptides - metabolism Animal Genetics and Genomics Animals Axons Behavioral Sciences Biological Techniques Biomedical and Life Sciences Biomedicine Cognition Cognitive ability Compaction Degradation Disease Models, Animal Gene sequencing Homeostasis Immune system Interferon Interferon-gamma - metabolism Life Sciences Mice Mice, Transgenic Microglia Microglia - metabolism MicroRNAs - genetics MicroRNAs - metabolism miRNA Neurobiology Neurodegenerative diseases Neurons and Cognition Neurosciences Pathogenesis Phagocytosis Phenotypes Plaque, Amyloid - metabolism Regulatory mechanisms (biology) Sequence analysis Signal Transduction - genetics Stat1 protein Therapeutic targets γ-Interferon |
| title | Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer’s disease |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-13T09%3A47%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Identification%20of%20a%20protective%20microglial%20state%20mediated%20by%20miR-155%20and%20interferon-%CE%B3%20signaling%20in%20a%20mouse%20model%20of%20Alzheimer%E2%80%99s%20disease&rft.jtitle=Nature%20neuroscience&rft.au=Yin,%20Zhuoran&rft.date=2023-07-01&rft.volume=26&rft.issue=7&rft.spage=1196&rft.epage=1207&rft.pages=1196-1207&rft.issn=1097-6256&rft.eissn=1546-1726&rft_id=info:doi/10.1038/s41593-023-01355-y&rft_dat=%3Cproquest_pubme%3E2833398324%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2833398324&rft_id=info:pmid/37291336&rfr_iscdi=true |