CD22 blockade restores homeostatic microglial phagocytosis in ageing brains
Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic...
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| Veröffentlicht in: | Nature (London) 2019-04, Vol.568 (7751), p.187-192 |
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| creator | Pluvinage, John V. Haney, Michael S. Smith, Benjamin A. H. Sun, Jerry Iram, Tal Bonanno, Liana Li, Lulin Lee, Davis P. Morgens, David W. Yang, Andrew C. Shuken, Steven R. Gate, David Scott, Madeleine Khatri, Purvesh Luo, Jian Bertozzi, Carolyn R. Bassik, Michael C. Wyss-Coray, Tony |
| description | Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR–Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-β oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.
CD22 inhibits microglial phagocytosis in the ageing brain, and treatment with a CD22-blocking antibody restores microglial homeostasis and cognitive function in ageing mice. |
| doi_str_mv | 10.1038/s41586-019-1088-4 |
| format | Article |
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CD22 inhibits microglial phagocytosis in the ageing brain, and treatment with a CD22-blocking antibody restores microglial homeostasis and cognitive function in ageing mice.</description><identifier>ISSN: 0028-0836</identifier><identifier>ISSN: 1476-4687</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-019-1088-4</identifier><identifier>PMID: 30944478</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Age ; Aging ; Aging (Biology) ; Aging - drug effects ; Aging - genetics ; Aging - physiology ; Alzheimer's disease ; Amyloid ; Animals ; Antibodies ; B cells ; Brain ; Brain - cytology ; Brain - drug effects ; Brain - physiology ; Brain research ; CD22 antigen ; Cell receptors ; Central nervous system ; Cognition - drug effects ; Cognition - physiology ; Cognitive ability ; CRISPR ; CRISPR-Associated Protein 9 - metabolism ; CRISPR-Cas Systems - genetics ; Debris ; Female ; Fibrils ; Flow cytometry ; Gene sequencing ; Genes ; Genetic analysis ; Genetic research ; Homeostasis ; Homeostasis - drug effects ; Homeostasis - genetics ; Humanities and Social Sciences ; Lymphocytes B ; Male ; Mice ; Mice, Inbred C57BL ; Microglia ; Microglia - cytology ; Microglia - drug effects ; multidisciplinary ; Myelin ; N-Acetylneuraminic Acid - chemistry ; N-Acetylneuraminic Acid - pharmacology ; Nervous system ; Nervous system diseases ; Neurodegeneration ; Neurodegenerative diseases ; Neurological diseases ; Oligomers ; Organic acids ; Phagocytes ; Phagocytosis ; Phagocytosis - drug effects ; Phagocytosis - genetics ; Physiological aspects ; Proteins ; Ribonucleic acid ; RNA ; RNA sequencing ; Science ; Science (multidisciplinary) ; Screens ; Sequence Analysis, RNA ; Sialic Acid Binding Ig-like Lectin 2 - antagonists & inhibitors ; Sialic Acid Binding Ig-like Lectin 2 - genetics ; Sialic Acid Binding Ig-like Lectin 2 - metabolism ; Synuclein ; Transcription</subject><ispartof>Nature (London), 2019-04, Vol.568 (7751), p.187-192</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2019</rights><rights>COPYRIGHT 2019 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Apr 11, 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c709t-b32c6a6b084ee198c1a78b504972953b29ed1ae1d45b16560d8ff92a4b3568153</citedby><cites>FETCH-LOGICAL-c709t-b32c6a6b084ee198c1a78b504972953b29ed1ae1d45b16560d8ff92a4b3568153</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-019-1088-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-019-1088-4$$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/30944478$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pluvinage, John V.</creatorcontrib><creatorcontrib>Haney, Michael S.</creatorcontrib><creatorcontrib>Smith, Benjamin A. H.</creatorcontrib><creatorcontrib>Sun, Jerry</creatorcontrib><creatorcontrib>Iram, Tal</creatorcontrib><creatorcontrib>Bonanno, Liana</creatorcontrib><creatorcontrib>Li, Lulin</creatorcontrib><creatorcontrib>Lee, Davis P.</creatorcontrib><creatorcontrib>Morgens, David W.</creatorcontrib><creatorcontrib>Yang, Andrew C.</creatorcontrib><creatorcontrib>Shuken, Steven R.</creatorcontrib><creatorcontrib>Gate, David</creatorcontrib><creatorcontrib>Scott, Madeleine</creatorcontrib><creatorcontrib>Khatri, Purvesh</creatorcontrib><creatorcontrib>Luo, Jian</creatorcontrib><creatorcontrib>Bertozzi, Carolyn R.</creatorcontrib><creatorcontrib>Bassik, Michael C.</creatorcontrib><creatorcontrib>Wyss-Coray, Tony</creatorcontrib><title>CD22 blockade restores homeostatic microglial phagocytosis in ageing brains</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR–Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-β oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.
CD22 inhibits microglial phagocytosis in the ageing brain, and treatment with a CD22-blocking antibody restores microglial homeostasis and cognitive function in ageing mice.</description><subject>Age</subject><subject>Aging</subject><subject>Aging (Biology)</subject><subject>Aging - drug effects</subject><subject>Aging - genetics</subject><subject>Aging - physiology</subject><subject>Alzheimer's disease</subject><subject>Amyloid</subject><subject>Animals</subject><subject>Antibodies</subject><subject>B cells</subject><subject>Brain</subject><subject>Brain - cytology</subject><subject>Brain - drug effects</subject><subject>Brain - physiology</subject><subject>Brain research</subject><subject>CD22 antigen</subject><subject>Cell receptors</subject><subject>Central nervous system</subject><subject>Cognition - drug effects</subject><subject>Cognition - physiology</subject><subject>Cognitive ability</subject><subject>CRISPR</subject><subject>CRISPR-Associated Protein 9 - metabolism</subject><subject>CRISPR-Cas Systems - genetics</subject><subject>Debris</subject><subject>Female</subject><subject>Fibrils</subject><subject>Flow cytometry</subject><subject>Gene sequencing</subject><subject>Genes</subject><subject>Genetic analysis</subject><subject>Genetic research</subject><subject>Homeostasis</subject><subject>Homeostasis - drug effects</subject><subject>Homeostasis - genetics</subject><subject>Humanities and Social Sciences</subject><subject>Lymphocytes B</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Microglia</subject><subject>Microglia - cytology</subject><subject>Microglia - drug effects</subject><subject>multidisciplinary</subject><subject>Myelin</subject><subject>N-Acetylneuraminic Acid - chemistry</subject><subject>N-Acetylneuraminic Acid - pharmacology</subject><subject>Nervous system</subject><subject>Nervous system diseases</subject><subject>Neurodegeneration</subject><subject>Neurodegenerative diseases</subject><subject>Neurological diseases</subject><subject>Oligomers</subject><subject>Organic acids</subject><subject>Phagocytes</subject><subject>Phagocytosis</subject><subject>Phagocytosis - drug effects</subject><subject>Phagocytosis - genetics</subject><subject>Physiological aspects</subject><subject>Proteins</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA sequencing</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Screens</subject><subject>Sequence Analysis, RNA</subject><subject>Sialic Acid Binding Ig-like Lectin 2 - antagonists & inhibitors</subject><subject>Sialic Acid Binding Ig-like Lectin 2 - genetics</subject><subject>Sialic Acid Binding Ig-like Lectin 2 - metabolism</subject><subject>Synuclein</subject><subject>Transcription</subject><issn>0028-0836</issn><issn>1476-4687</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1kl-L1DAUxYMo7jj6AXyRoi-KdE3SNE1ehGH8t7go6IqPIU1vO1nbZDZpxf32Zph1dyuzBBLI_d2TXM5B6CnBxwQX4k1kpBQ8x0TmBAuRs3toQVjFc8ZFdR8tMKYix6LgR-hRjOcY45JU7CE6KrBkjFVigT6v31Ga1b03v3QDWYA4-rRlGz-Aj6MerckGa4Lveqv7bLvRnTeXo482ZtZlugPruqwO2rr4GD1odR_hydW5RD8-vD9bf8pPv348Wa9Oc1NhOeZ1QQ3XvMaCARApDNGVqEvMZEVlWdRUQkM0kIaVNeElx41oW0k1q4uSC1IWS_R2r7ud6gEaA24MulfbYAcdLpXXVs0rzm5U538rXlaMEJkEXl4JBH8xpZHVYKOBvtcO_BQVpbgghaRpW6IX_6HnfgoujZeopEU4Z8UN1ekelHWtT--anahalYJiipnYUfkBqgMH6ZPeQWvT9Yx_foA3W3uhbkPHB6C0Gki-HVR9NWtIzAh_xk5PMaqT79_m7Ou72dXZz_WXOU32dIpLjAHaa0sIVrvAqn1gVQqs2gVWsdTz7LaX1x3_EpoAugdiKrkOwo0Bd6v-BUJp8Hw</recordid><startdate>20190401</startdate><enddate>20190401</enddate><creator>Pluvinage, John V.</creator><creator>Haney, Michael S.</creator><creator>Smith, Benjamin A. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pluvinage, John V.</au><au>Haney, Michael S.</au><au>Smith, Benjamin A. H.</au><au>Sun, Jerry</au><au>Iram, Tal</au><au>Bonanno, Liana</au><au>Li, Lulin</au><au>Lee, Davis P.</au><au>Morgens, David W.</au><au>Yang, Andrew C.</au><au>Shuken, Steven R.</au><au>Gate, David</au><au>Scott, Madeleine</au><au>Khatri, Purvesh</au><au>Luo, Jian</au><au>Bertozzi, Carolyn R.</au><au>Bassik, Michael C.</au><au>Wyss-Coray, Tony</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CD22 blockade restores homeostatic microglial phagocytosis in ageing brains</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2019-04-01</date><risdate>2019</risdate><volume>568</volume><issue>7751</issue><spage>187</spage><epage>192</epage><pages>187-192</pages><issn>0028-0836</issn><issn>1476-4687</issn><eissn>1476-4687</eissn><abstract>Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR–Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-β oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.
CD22 inhibits microglial phagocytosis in the ageing brain, and treatment with a CD22-blocking antibody restores microglial homeostasis and cognitive function in ageing mice.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30944478</pmid><doi>10.1038/s41586-019-1088-4</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2019-04, Vol.568 (7751), p.187-192 |
| issn | 0028-0836 1476-4687 1476-4687 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6574119 |
| source | MEDLINE; SpringerLink Journals; Nature Journals Online |
| subjects | Age Aging Aging (Biology) Aging - drug effects Aging - genetics Aging - physiology Alzheimer's disease Amyloid Animals Antibodies B cells Brain Brain - cytology Brain - drug effects Brain - physiology Brain research CD22 antigen Cell receptors Central nervous system Cognition - drug effects Cognition - physiology Cognitive ability CRISPR CRISPR-Associated Protein 9 - metabolism CRISPR-Cas Systems - genetics Debris Female Fibrils Flow cytometry Gene sequencing Genes Genetic analysis Genetic research Homeostasis Homeostasis - drug effects Homeostasis - genetics Humanities and Social Sciences Lymphocytes B Male Mice Mice, Inbred C57BL Microglia Microglia - cytology Microglia - drug effects multidisciplinary Myelin N-Acetylneuraminic Acid - chemistry N-Acetylneuraminic Acid - pharmacology Nervous system Nervous system diseases Neurodegeneration Neurodegenerative diseases Neurological diseases Oligomers Organic acids Phagocytes Phagocytosis Phagocytosis - drug effects Phagocytosis - genetics Physiological aspects Proteins Ribonucleic acid RNA RNA sequencing Science Science (multidisciplinary) Screens Sequence Analysis, RNA Sialic Acid Binding Ig-like Lectin 2 - antagonists & inhibitors Sialic Acid Binding Ig-like Lectin 2 - genetics Sialic Acid Binding Ig-like Lectin 2 - metabolism Synuclein Transcription |
| title | CD22 blockade restores homeostatic microglial phagocytosis in ageing brains |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T07%3A24%3A59IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=CD22%20blockade%20restores%20homeostatic%20microglial%20phagocytosis%20in%20ageing%20brains&rft.jtitle=Nature%20(London)&rft.au=Pluvinage,%20John%20V.&rft.date=2019-04-01&rft.volume=568&rft.issue=7751&rft.spage=187&rft.epage=192&rft.pages=187-192&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/s41586-019-1088-4&rft_dat=%3Cgale_pubme%3EA582020483%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2211916643&rft_id=info:pmid/30944478&rft_galeid=A582020483&rfr_iscdi=true |