{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:50:05Z","timestamp":1792525805208,"version":"4.5.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T00:00:00Z","timestamp":1646956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Perioperative neurocognitive disorders (PNDs) are common complications of surgical patients, which can lead to prolonged hospitalization, increased complications, and decreased independence and quality of life. However, the underlying molecular mechanisms of PND remain largely obscure. Microglia activation and synapse loss were observed in PND. Cluster of differentiation 47 (CD47), which can bind to its receptor signal regulatory protein alpha (SIRP\u03b1) and generate \u201cdo not eat me\u201d signal, protects synapses from excessive pruning. Therefore, we aimed to evaluate the potential role of CD47\u2013SIRP\u03b1 signaling in PND.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The tibial fracture surgery was performed in aged C57BL\/6 mice for PND model establishment. The expression of CD47 and SIRP\u03b1 in the hippocampus was assessed. Synaptic plasticity, dendritic spine density, microglial engulfment, and hippocampal-dependent memory function were evaluated after model establishment and intervention with SIRP\u03b1 overexpression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CD47 and SIRP\u03b1 expression in the hippocampus were both decreased after the surgery. SIRP\u03b1 overexpression showed reduced engulfment within host microglia, but a total effect of excessive synapse engulfment decreased dendritic spine density and post-synaptic density protein 95 (PSD95) expression. SIRP\u03b1 overexpression could not improve the synaptic dysfunction and cognitive impairment in PND. In addition, SIRP\u03b1 overexpression led to increased CD47 and Iba1 expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Anesthesia and surgery affect CD47\u2013SIRP\u03b1 signaling. SIRP\u03b1 overexpression could not ameliorate the cognitive impairment in PND mice. One reason may be that the increased Iba1 expression leads to a total effect of excessive synapse engulfment, which results in decreased dendritic spine density and PSD95 expression.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnins.2022.788675","type":"journal-article","created":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T07:17:52Z","timestamp":1646983072000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Anomalous Levels of CD47\/Signal Regulatory Protein Alpha in the Hippocampus Lead to Excess Microglial Engulfment in Mouse Model of Perioperative Neurocognitive Disorders"],"prefix":"10.3389","volume":"16","author":[{"given":"Min","family":"Shui","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changwei","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7181","DOI":"10.1128\/MCB.25.16.7181-7192.2005","article-title":"Signal regulatory protein alpha ligation induces macrophage nitric oxide production through JAK\/STAT- and phosphatidylinositol 3-kinase\/Rac1\/NAPDH oxidase\/H2O2-dependent pathways.","volume":"25","author":"Alblas","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1146\/annurev-immunol-032713-120142","article-title":"The interaction between signal regulatory protein alpha (SIRP\u03b1) and CD47: structure, function, and therapeutic target.","volume":"32","author":"Barclay","year":"2014","journal-title":"Annu. Rev. Immunol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1007\/s11481-018-9793-6","article-title":"The neuro-immune-regulators (NIREGs) promote tissue resilience; a vital component of the host\u2019s defense strategy against neuroinflammation.","volume":"13","author":"Bedoui","year":"2018","journal-title":"J. Neuroimmune Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1186\/s12974-020-01886-2","article-title":"Histamine 2\/3 receptor agonists alleviate perioperative neurocognitive disorders by inhibiting microglia activation through the PI3K\/AKT\/FoxO1 pathway in aged rats.","volume":"17","author":"Chen","year":"2020","journal-title":"J. Neuroinflam."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2030","DOI":"10.1038\/s41467-021-22301-1","article-title":"Loss of microglial SIRP\u03b1 promotes synaptic pruning in preclinical models of neurodegeneration.","volume":"12","author":"Ding","year":"2021","journal-title":"Nat. Commun."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1016\/j.bja.2017.11.087","article-title":"Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018.","volume":"121","author":"Evered","year":"2018","journal-title":"Br. J. Anaesth"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e91229","DOI":"10.1172\/jci.insight.91229","article-title":"Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice.","volume":"2","author":"Feng","year":"2017","journal-title":"JCI Insight"},{"key":"B8","doi-asserted-by":"publisher","first-page":"943","DOI":"10.3390\/molecules26133943","article-title":"CD47 in the brain and neurodegeneration: an update on the role in neuroinflammatory pathways.","volume":"26","author":"Gheibihayat","year":"2021","journal-title":"Molecules"},{"key":"B9","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/1742-2094-8-24","article-title":"Myelin down-regulates myelin phagocytosis by microglia and macrophages through interactions between CD47 on myelin and SIRP\u03b1 (signal regulatory protein-\u03b1) on phagocytes.","volume":"8","author":"Gitik","year":"2011","journal-title":"J. Neuroinflam."},{"key":"B10","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1146\/annurev-cellbio-100616-060509","article-title":"Microglia and the brain: complementary partners in development and disease.","volume":"34","author":"Hammond","year":"2018","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1084\/jem.20101974","article-title":"Janus-like opposing roles of CD47 in autoimmune brain inflammation in humans and mice.","volume":"209","author":"Han","year":"2012","journal-title":"J. Exp. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/j.bja.2017.11.096","article-title":"Interleukin-6 is both necessary and sufficient to produce perioperative neurocognitive disorder in mice.","volume":"120","author":"Hu","year":"2018","journal-title":"Br. J. Anaesth"},{"key":"B13","doi-asserted-by":"publisher","first-page":"100862","DOI":"10.1016\/j.tranon.2020.100862","article-title":"Regulation of CD47 expression in cancer cells.","volume":"13","author":"Huang","year":"2020","journal-title":"Transl. Oncol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.brainres.2014.10.034","article-title":"Theta-burst LTP.","volume":"1621","author":"Larson","year":"2015","journal-title":"Brain Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.neuron.2018.09.017","article-title":"CD47 protects synapses from excess microglia-mediated pruning during development.","volume":"100","author":"Lehrman","year":"2018","journal-title":"Neuron"},{"key":"B16","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/s12974-021-02089-z","article-title":"Sirtuin 3 protects against anesthesia\/surgery-induced cognitive decline in aged mice by suppressing hippocampal neuroinflammation.","volume":"18","author":"Liu","year":"2021","journal-title":"J. Neuroinflam."},{"key":"B17","doi-asserted-by":"publisher","first-page":"134310","DOI":"10.1016\/j.neulet.2019.134310","article-title":"Targeting microglia with lentivirus and AAV: recent advances and remaining challenges.","volume":"707","author":"Maes","year":"2019","journal-title":"Neurosci. Lett."},{"key":"B18","doi-asserted-by":"publisher","first-page":"104901","DOI":"10.1016\/j.neuint.2020.104901","article-title":"Synaptic elimination by microglia and disturbed higher brain functions.","volume":"142","author":"Miyanishi","year":"2021","journal-title":"Neurochem. Int."},{"key":"B19","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/S0968-0004(03)00091-4","article-title":"The \u2018Shp\u2019ing news: SH2 domain-containing tyrosine phosphatases in cell signaling.","volume":"28","author":"Neel","year":"2003","journal-title":"Trends Biochem. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2702","DOI":"10.1523\/JNEUROSCI.5173-04.2005","article-title":"Differential localization of Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 and CD47 and its molecular mechanisms in cultured hippocampal neurons.","volume":"25","author":"Ohnishi","year":"2005","journal-title":"J. Neurosci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"614619","DOI":"10.1155\/2013\/614619","article-title":"CD47: a cell surface glycoprotein which regulates multiple functions of hematopoietic cells in health and disease.","volume":"2013","author":"Oldenborg","year":"2013","journal-title":"ISRN Hematol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1038\/s41586-019-1088-4","article-title":"CD22 blockade restores homeostatic microglial phagocytosis in ageing brains.","volume":"568","author":"Pluvinage","year":"2019","journal-title":"Nature"},{"key":"B23","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1186\/s12974-020-01939-6","article-title":"Hippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments.","volume":"17","author":"Reverchon","year":"2020","journal-title":"J. Neuroinflam."},{"key":"B24","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1038\/d41586-018-07165-8","article-title":"A \u2018don\u2019t eat me\u2019 immune signal protects neuronal connections.","volume":"563","author":"Rivest","year":"2018","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","first-page":"671499","DOI":"10.3389\/fnagi.2021.671499","article-title":"The role of microglia in perioperative neuroinflammation and neurocognitive disorders.","volume":"13","author":"Saxena","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"51482","DOI":"10.3791\/51482","article-title":"An engulfment assay: a protocol to assess interactions between CNS phagocytes and neurons.","volume":"8","author":"Schafer","year":"2014","journal-title":"J. Vis. Exp."},{"key":"B27","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.neubiorev.2017.11.011","article-title":"Post-operative cognitive dysfunction: an exploration of the inflammatory hypothesis and novel therapies.","volume":"84","author":"Skvarc","year":"2018","journal-title":"Neurosci. Biobehav. Rev."},{"key":"B28","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1213\/ANE.0000000000004053","article-title":"Neuroinflammation and perioperative neurocognitive disorders.","volume":"128","author":"Subramaniyan","year":"2019","journal-title":"Anesth. Analg."},{"key":"B29","doi-asserted-by":"publisher","first-page":"7781","DOI":"10.4049\/jimmunol.175.12.7781","article-title":"Signal regulatory proteins in the immune system.","volume":"175","author":"van Beek","year":"2005","journal-title":"J. Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.immuni.2019.12.004","article-title":"Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease.","volume":"52","author":"Werneburg","year":"2020","journal-title":"Immunity"},{"key":"B31","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1186\/s12974-018-1292-4","article-title":"Complement activation contributes to perioperative neurocognitive disorders in mice.","volume":"15","author":"Xiong","year":"2018","journal-title":"J. Neuroinflam."},{"key":"B32","doi-asserted-by":"publisher","first-page":"9741","DOI":"10.1523\/JNEUROSCI.0681-17.2017","article-title":"Increased GSNOR expression during aging impairs cognitive function and decreases S-nitrosation of CaMKII\u03b1.","volume":"37","author":"Zhang","year":"2017","journal-title":"J. Neurosci."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2022.788675\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T07:17:55Z","timestamp":1646983075000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2022.788675\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,11]]},"references-count":32,"alternative-id":["10.3389\/fnins.2022.788675"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2022.788675","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,11]]},"article-number":"788675"}}