{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:26:47Z","timestamp":1790630807888,"version":"4.1.0"},"reference-count":142,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T00:00:00Z","timestamp":1662422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is an irreversible neurodegenerative disease mainly characterized by memory loss and cognitive decline. The etiology of AD is complex and remains incompletely understood. In recent years, genome-wide association studies (GWAS) have increasingly highlighted the central role of microglia in AD pathology. As a trans-membrane receptor specifically present on the microglia in the central nervous system, phosphatidylinositol-specific phospholipase C gamma 2 (PLC\u03b32) plays an important role in neuroinflammation. GWAS data and corresponding pathological research have explored the effects of <jats:italic>PLCG2<\/jats:italic> variants on amyloid burden and tau pathologies that underline AD. The link between PLC\u03b32 and other AD-related effectors in human and mouse microglia has also been established, placing PLC\u03b32 downstream of the triggering receptor expressed on myeloid cells 2 (TREM2), toll-like receptor 4 (TLR4), Bruton\u2019s tyrosine kinase (BTK), and colony-stimulating factor 1 receptor (CSF1R). Because the research on PLC\u03b32\u2019s role in AD is still in its early stages, few articles have been published, therefore in this paper, we integrate the relevant research published to date, review the structural features, expression patterns, and related pathways of PLC\u03b32, and summarize the recent studies on important <jats:italic>PLCG2<\/jats:italic> variants related to AD. Furthermore, the possibility and challenge of using PLC\u03b32 to develop therapeutic drugs for AD are also discussed.<\/jats:p>","DOI":"10.3389\/fcell.2022.999061","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T08:01:32Z","timestamp":1662451292000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["PLC\u03b32 impacts microglia-related effectors revealing variants and pathways important in Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"10","author":[{"given":"Ke","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beibei","family":"Ran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1002\/art.30280","article-title":"A novel N-ethyl-N-nitrosourea-induced mutation in phospholipase C\u03b32 causes inflammatory arthritis, metabolic defects, and male infertility in vitro in a murine model.","volume":"63","author":"Abe","year":"2011","journal-title":"Arthritis Rheum."},{"key":"B2","doi-asserted-by":"publisher","first-page":"74","DOI":"10.3389\/fimmu.2017.00074","article-title":"A comprehensive gene expression meta-analysis identifies novel immune signatures in rheumatoid arthritis patients","volume":"8","author":"Afroz","year":"2017","journal-title":"Front. Immunol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1182\/blood-2016-06-719294","article-title":"Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia","volume":"129","author":"Ahn","year":"2017","journal-title":"Blood"},{"key":"B4","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1038\/s41593-020-0650-6","article-title":"Alzheimer's-associated PLC\u03b32 is a signaling node required for both TREM2 function and the inflammatory response in human microglia.","volume":"23","author":"Andreone","year":"2020","journal-title":"Nat. Neurosci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1016\/j.cell.2009.05.028","article-title":"The selectivity of receptor tyrosine kinase signaling is controlled by a secondary SH2 domain binding site","volume":"138","author":"Bae","year":"2009","journal-title":"Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.jbior.2016.09.006","article-title":"Phospholipase C\u03b3 in Toll-like receptor-mediated inflammation and innate immunity.","volume":"63","author":"Bae","year":"2017","journal-title":"Adv. Biol. Regul."},{"key":"B7","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.bbi.2016.10.012","article-title":"Toll-like receptor 4-dependent glial cell activation mediates the impairment in memory establishment induced by beta-amyloid oligomers in an acute mouse model of Alzheimer's disease","volume":"60","author":"Balducci","year":"2017","journal-title":"Brain Behav. Immun."},{"key":"B8","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/s41588-022-01024-z","article-title":"New insights into the genetic etiology of Alzheimer\u2019s disease and related dementias","volume":"54","author":"Bellenguez","year":"2022","journal-title":"Nat. Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1111\/j.1749-6632.1995.tb26646.x","article-title":"Inositol trisphosphate and calcium signaling","volume":"766","author":"Berridge","year":"1995","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1097\/RMR.0000000000000222","article-title":"The radiogenomics of late-onset alzheimer disease","volume":"28","author":"Bonham","year":"2019","journal-title":"Top. Magn. Reson. Imaging"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1093\/jnen\/61.11.1013","article-title":"Broad expression of Toll-like receptors in the human central nervous system","volume":"61","author":"Bsibsi","year":"2002","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2062","DOI":"10.1016\/j.str.2012.09.005","article-title":"Structural and functional integration of the PLC\u03b3 interaction domains critical for regulatory mechanisms and signaling deregulation.","volume":"20","author":"Bunney","year":"2012","journal-title":"Structure"},{"key":"B13","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1111\/j.1471-4159.2011.07594.x","article-title":"Resveratrol mitigates lipopolysaccharide- and A\u03b2-mediated microglial inflammation by inhibiting the TLR4\/NF-\u03baB\/STAT signaling cascade.","volume":"120","author":"Capiralla","year":"2012","journal-title":"J. Neurochem."},{"key":"B14","doi-asserted-by":"publisher","first-page":"108843","DOI":"10.1016\/j.celrep.2021.108843","article-title":"The AD tau core spontaneously self-assembles and recruits full-length tau to filaments","volume":"34","author":"Carlomagno","year":"2021","journal-title":"Cell Rep."},{"key":"B15","doi-asserted-by":"publisher","first-page":"17762","DOI":"10.1038\/s41598-017-17999-3","article-title":"Comparative profiling of cortical gene expression in Alzheimer's disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation","volume":"7","author":"Castillo","year":"2017","journal-title":"Sci. Rep."},{"key":"B16","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1002\/art.38961","article-title":"Connecting two pathways through Ca2+ signaling: NLRP3 inflammasome activation induced by a hypermorphic PLCG2 mutation","volume":"67","author":"Chae","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"71","DOI":"10.3233\/JAD-201140","article-title":"PLCG2 rs72824905 variant reduces the risk of alzheimer's disease and multiple sclerosis","volume":"80","author":"Chen","year":"2021","journal-title":"J. Alzheimers Dis."},{"key":"B18","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1038\/ni.3642","article-title":"Themis2 lowers the threshold for B cell activation during positive selection","volume":"18","author":"Cheng","year":"2017","journal-title":"Nat. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"3704","DOI":"10.1074\/jbc.C111.328559","article-title":"Phospholipase C\u03b3-2 and intracellular calcium are required for lipopolysaccharide-induced Toll-like receptor 4 (TLR4) endocytosis and interferon regulatory factor 3 (IRF3) activation.","volume":"287","author":"Chiang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B20","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.tins.2016.03.005","article-title":"Emerging roles for CSF-1 receptor and its ligands in the nervous system","volume":"39","author":"Chitu","year":"2016","journal-title":"Trends Neurosci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jneuroim.2018.02.015","article-title":"The roles of macrophages and microglia in multiple sclerosis and experimental autoimmune encephalomyelitis","volume":"318","author":"Chu","year":"2018","journal-title":"J. Neuroimmunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"3285","DOI":"10.1172\/JCI25247","article-title":"P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model","volume":"115","author":"Cirrito","year":"2005","journal-title":"J. Clin. Invest."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12577","article-title":"The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model","author":"Claes","year":"2022","journal-title":"Alzheimer's. Dementia"},{"key":"B24","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/s13024-018-0289-x","article-title":"ABI3 and PLCG2 missense variants as risk factors for neurodegenerative diseases in Caucasians and African Americans","volume":"13","author":"Conway","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"B25","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/s41398-019-0394-9","article-title":"Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease","volume":"9","author":"Dalmasso","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"B26","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.immuni.2006.11.012","article-title":"Bruton's tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing","volume":"26","author":"de Gorter","year":"2007","journal-title":"Immunity"},{"key":"B27","doi-asserted-by":"publisher","first-page":"4602","DOI":"10.2174\/0929867324666171012112026","article-title":"Nanotechnology in personalized medicine: A promising tool for alzheimer's disease treatment","volume":"25","author":"De Matteis","year":"2018","journal-title":"Curr. Med. Chem."},{"key":"B28","doi-asserted-by":"publisher","first-page":"3417","DOI":"10.1038\/s41467-021-22491-8","article-title":"Common variants in Alzheimer's disease and risk stratification by polygenic risk scores","volume":"12","author":"de Rojas","year":"2021","journal-title":"Nat. Commun."},{"key":"B29","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1007\/978-1-4939-7868-7_4","article-title":"Genome-wide association studies","volume":"1793","author":"Dehghan","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"E3776","DOI":"10.3390\/ijms20153776","article-title":"Perspectives for ezrin and radixin in astrocytes: Kinases, functions and pathology","volume":"20","author":"Derouiche","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2199","DOI":"10.3389\/fimmu.2019.02199","article-title":"CSF1R ligands IL-34 and CSF1 are differentially required for microglia development and maintenance in white and gray matter brain regions","volume":"10","author":"Easley-Neal","year":"2019","journal-title":"Front. Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s13024-017-0184-x","article-title":"Late onset Alzheimer's disease genetics implicates microglial pathways in disease risk","volume":"12","author":"Efthymiou","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"B33","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.neuron.2014.02.040","article-title":"Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain","volume":"82","author":"Elmore","year":"2014","journal-title":"Neuron"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1240","DOI":"10.1128\/MCB.01408-10","article-title":"Membrane environment exerts an important influence on rac-mediated activation of phospholipase C\u03b32.","volume":"31","author":"Everett","year":"2011","journal-title":"Mol. Cell. Biol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1093\/emboj\/17.2.414","article-title":"Activation of phospholipase C gamma by PI 3-kinase-induced PH domain-mediated membrane targeting","volume":"17","author":"Falasca","year":"1998","journal-title":"EMBO J."},{"key":"B36","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1016\/j.bbalip.2010.05.004","article-title":"Lipids in alzheimer's disease: A century-old story","volume":"1801","author":"Foley","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"B37","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1016\/j.celrep.2017.12.066","article-title":"Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of alzheimer's disease not evident in mouse models","volume":"22","author":"Friedman","year":"2018","journal-title":"Cell Rep."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1172\/JCI25100","article-title":"The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease","volume":"115","author":"Gandy","year":"2005","journal-title":"J. Clin. Invest."},{"key":"B39","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1001\/archpsyc.63.2.168","article-title":"Role of genes and environments for explaining Alzheimer disease","volume":"63","author":"Gatz","year":"2006","journal-title":"Arch. Gen. Psychiatry"},{"key":"B40","doi-asserted-by":"publisher","first-page":"2813","DOI":"10.1002\/1873-3468.12313","article-title":"The activation of \u03bc-opioid receptor potentiates LPS-induced NF-kB promoting an inflammatory phenotype in microglia","volume":"590","author":"Gessi","year":"2016","journal-title":"FEBS Lett."},{"key":"B41","doi-asserted-by":"publisher","first-page":"e0150411","DOI":"10.1371\/journal.pone.0150411","article-title":"A gain-of-function mutation in the Plcg2 gene protects mice from Helicobacter felis-induced gastric MALT lymphoma","volume":"11","author":"Gossmann","year":"2016","journal-title":"Plos One"},{"key":"B42","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1159\/000487641","article-title":"Mutual relationship between tau and central insulin signalling: Consequences for AD and tauopathies?","volume":"107","author":"Gratuze","year":"2018","journal-title":"Neuroendocrinology"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.3389\/fphar.2019.01245","article-title":"Cerebrolysin ameliorates focal cerebral ischemia injury through neuroinflammatory inhibition via CREB\/PGC-1 alpha pathway","volume":"10","author":"Guan","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1056\/NEJMoa1211851","article-title":"TREM2 variants in Alzheimer's disease","volume":"368","author":"Guerreiro","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"B45","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.ceb.2019.12.007","article-title":"Novel roles of phosphoinositides in signaling, lipid transport, and disease","volume":"63","author":"Hammond","year":"2020","journal-title":"Curr. Opin. Cell Biol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"23645","DOI":"10.1074\/jbc.M703269200","article-title":"Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis","volume":"282","author":"Hanger","year":"2007","journal-title":"J. Biol. Chem."},{"key":"B47","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1083\/jcb.201709069","article-title":"Microglia in Alzheimer's disease","volume":"217","author":"Hansen","year":"2018","journal-title":"J. Cell Biol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.4049\/jimmunol.165.4.1738","article-title":"Cutting edge: Essential role of phospholipase C-gamma 2 in B cell development and function","volume":"165","author":"Hashimoto","year":"2000","journal-title":"J. Immunol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"77sr71","DOI":"10.1126\/scitranslmed.3002369","article-title":"Alzheimer's disease: The challenge of the second century","volume":"3","author":"Holtzman","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"B50","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1186\/s12974-020-01862-w","article-title":"Rh-CSF1 attenuates neuroinflammation via the CSF1R\/PLCG2\/PKC\u03b5 pathway in a rat model of neonatal HIE.","volume":"17","author":"Hu","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"B51","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.cub.2009.12.019","article-title":"Activation of TRP channels by protons and phosphoinositide depletion in Drosophila photoreceptors","volume":"20","author":"Huang","year":"2010","journal-title":"Curr. Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.bbr.2016.08.047","article-title":"TLR4 is a link between diabetes and Alzheimer's disease","volume":"316","author":"Huang","year":"2017","journal-title":"Behav. Brain Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1016\/s0959-440x(97)80122-4","article-title":"Protein kinase C and phospholipase C: Bilayer interactions and regulation","volume":"7","author":"Hurley","year":"1997","journal-title":"Curr. Opin. Struct. Biol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.clineuro.2009.08.020","article-title":"CSF tau protein is a useful marker for effective treatment of superficial siderosis of the central nervous system: Two case reports","volume":"112","author":"Ikeda","year":"2010","journal-title":"Clin. Neurol. Neurosurg."},{"key":"B55","doi-asserted-by":"publisher","first-page":"100905","DOI":"10.1016\/j.jbc.2021.100905","article-title":"The role of PLC\u03b32 in immunological disorders, cancer, and neurodegeneration.","volume":"297","author":"Jackson","year":"2021","journal-title":"J. Biol. Chem."},{"key":"B56","doi-asserted-by":"publisher","first-page":"6341","DOI":"10.1007\/s12035-019-1518-1","article-title":"Effect of the HDAC inhibitor, sodium butyrate, on neurogenesis in a rat model of neonatal hypoxia-ischemia: Potential mechanism of action","volume":"56","author":"Jaworska","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s12974-017-0835-4","article-title":"The Alzheimer's disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway","volume":"14","author":"Jendresen","year":"2017","journal-title":"J. Neuroinflammation"},{"key":"B58","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/1742-2094-5-23","article-title":"Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease","volume":"5","author":"Jin","year":"2008","journal-title":"J. Neuroinflammation"},{"key":"B59","doi-asserted-by":"publisher","first-page":"1645","DOI":"10.1038\/leu.2017.110","article-title":"PLCG2 C2 domain mutations co-occur with BTK and PLCG2 resistance mutations in chronic lymphocytic leukemia undergoing ibrutinib treatment","volume":"31","author":"Jones","year":"2017","journal-title":"Leukemia"},{"key":"B60","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1146\/annurev.immunol.23.021704.115606","article-title":"B cell signaling and tumorigenesis","volume":"23","author":"Jumaa","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"B61","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1146\/annurev-physiol-030212-183750","article-title":"Mammalian phospholipase C","volume":"75","author":"Kadamur","year":"2013","journal-title":"Annu. Rev. Physiol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1016\/j.cell.2006.03.047","article-title":"Phosphoinositide-mediated adaptor recruitment controls toll-like receptor signaling","volume":"125","author":"Kagan","year":"2006","journal-title":"Cell"},{"key":"B63","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.biopsych.2014.05.006","article-title":"Alzheimer's disease risk genes and mechanisms of disease pathogenesis","volume":"77","author":"Karch","year":"2015","journal-title":"Biol. Psychiatry"},{"key":"B64","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1042\/EBC20200041","article-title":"Phosphatidylinositol(4, 5)bisphosphate: Diverse functions at the plasma membrane","volume":"64","author":"Katan","year":"2020","journal-title":"Essays Biochem."},{"key":"B65","doi-asserted-by":"publisher","first-page":"461","DOI":"10.3389\/fimmu.2014.00461","article-title":"Toll-like receptor signaling pathways","volume":"5","author":"Kawasaki","year":"2014","journal-title":"Front. Immunol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1007\/s11481-019-09839-0","article-title":"Inhibition of Bruton's tyrosine kinase modulates microglial phagocytosis: Therapeutic implications for alzheimer's disease","volume":"14","author":"Keaney","year":"2019","journal-title":"J. Neuroimmune Pharmacol."},{"key":"B67","doi-asserted-by":"publisher","first-page":"9986","DOI":"10.1128\/MCB.24.22.9986-9999.2004","article-title":"Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2","volume":"24","author":"Kim","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"243ra86","DOI":"10.1126\/scitranslmed.3009093","article-title":"TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis","volume":"6","author":"Kleinberger","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"B69","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1007\/s00401-020-02138-6","article-title":"PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment","volume":"139","author":"Kleineidam","year":"2020","journal-title":"Acta Neuropathol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1016\/j.tibs.2014.09.004","article-title":"Dysfunction of phospholipase C\u03b3 in immune disorders and cancer.","volume":"39","author":"Koss","year":"2014","journal-title":"Trends biochem. Sci."},{"key":"B71","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.immuni.2017.08.008","article-title":"The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases","volume":"47","author":"Krasemann","year":"2017","journal-title":"Immunity"},{"key":"B72","doi-asserted-by":"publisher","first-page":"5239","DOI":"10.1007\/s12035-021-02477-9","article-title":"Role of TREM2 in alzheimer's disease: A long road ahead","volume":"58","author":"Kulkarni","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1038\/s41588-019-0358-2","article-title":"Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A\u03b2, tau, immunity and lipid processing","volume":"51","author":"Kunkle","year":"2019","journal-title":"Nat. Genet."},{"key":"B74","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1080\/17474086.2018.1435268","article-title":"Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?","volume":"11","author":"Lampson","year":"2018","journal-title":"Expert Rev. Hematol."},{"key":"B75","doi-asserted-by":"publisher","first-page":"924","DOI":"10.1126\/science.1234114","article-title":"Response to comments on \"ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models","volume":"340","author":"Landreth","year":"2013","journal-title":"Science"},{"key":"B76","doi-asserted-by":"publisher","first-page":"361","DOI":"10.5483\/bmbrep.2014.47.7.088","article-title":"Phosphoinositide turnover in Toll-like receptor signaling and trafficking","volume":"47","author":"Le","year":"2014","journal-title":"BMB Rep."},{"key":"B77","doi-asserted-by":"publisher","first-page":"e9027","DOI":"10.15252\/emmm.201809027","article-title":"High-affinity interactions and signal transduction between A beta oligomers and TREM2","volume":"10","author":"Lessard","year":"2018","journal-title":"EMBO Mol. Med."},{"key":"B78","doi-asserted-by":"publisher","first-page":"6168","DOI":"10.1007\/s12035-019-1507-4","article-title":"Pathological alterations of tau in alzheimer's disease and 3xTg-AD mouse brains","volume":"56","author":"Li","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"B79","doi-asserted-by":"publisher","first-page":"7397","DOI":"10.1007\/s00018-021-03986-5","article-title":"Genomics of Alzheimer's disease implicates the innate and adaptive immune systems","volume":"78","author":"Li","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"B80","doi-asserted-by":"publisher","first-page":"102607","DOI":"10.1016\/j.ebiom.2019.102607","article-title":"Structural insights and activating mutations in diverse pathologies define mechanisms of deregulation for phospholipase C gamma enzymes","volume":"51","author":"Liu","year":"2020","journal-title":"EBioMedicine"},{"key":"B81","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1002\/glia.1072","article-title":"Inflammatory repertoire of Alzheimer's disease and nondemented elderly microglia in vitro","volume":"35","author":"Lue","year":"2001","journal-title":"Glia"},{"key":"B82","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1084\/jem.20120412","article-title":"Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival","volume":"210","author":"Luo","year":"2013","journal-title":"J. Exp. Med."},{"key":"B83","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/s13024-021-00436-5","article-title":"TREM2\/PLC\u03b32 signalling in immune cells: Function, structural insight, and potential therapeutic modulation","volume":"16","author":"Magno","year":"2021","journal-title":"Mol. Neurodegener."},{"key":"B84","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s13195-019-0469-0","article-title":"Alzheimer\u2019s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph","volume":"11","author":"Magno","year":"2019","journal-title":"Alzheimers Res. Ther."},{"key":"B85","doi-asserted-by":"publisher","first-page":"e105603","DOI":"10.15252\/embj.2020105603","article-title":"PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease-protective variant PLC\u03b32 R522","volume":"40","author":"Maguire","year":"2021","journal-title":"Embo J."},{"key":"B86","doi-asserted-by":"publisher","first-page":"2869","DOI":"10.1172\/JCI28775","article-title":"PLCgamma2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2","volume":"116","author":"Mao","year":"2006","journal-title":"J. Clin. Invest."},{"key":"B87","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1007\/s10875-020-00794-7","article-title":"Severe autoinflammatory manifestations and antibody deficiency due to novel hypermorphic PLCG2 mutations","volume":"40","author":"Martin-Nalda","year":"2020","journal-title":"J. Clin. Immunol."},{"key":"B88","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.celrep.2014.12.041","article-title":"A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology","volume":"10","author":"Matarin","year":"2015","journal-title":"Cell Rep."},{"key":"B89","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1083\/jcb.153.3.599","article-title":"Real time fluorescence imaging of PLC gamma translocation and its interaction with the epidermal growth factor receptor","volume":"153","author":"Matsuda","year":"2001","journal-title":"J. Cell Biol."},{"key":"B90","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1007\/s10875-015-0177-x","article-title":"Plaid: A syndrome of complex patterns of disease and unique phenotypes","volume":"35","author":"Milner","year":"2015","journal-title":"J. Clin. Immunol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"1392","DOI":"10.1016\/j.cellsig.2015.03.023","article-title":"Is hydrogen ion (H+) the real second messenger in calcium signalling?","volume":"27","author":"Molinari","year":"2015","journal-title":"Cell. Signal."},{"key":"B92","doi-asserted-by":"publisher","first-page":"3118","DOI":"10.1182\/blood-2009-11-254185","article-title":"Tyrosine kinase Btk regulates E-selectin-mediated integrin activation and neutrophil recruitment by controlling phospholipase C (PLC) gamma2 and PI3Kgamma pathways","volume":"115","author":"Mueller","year":"2010","journal-title":"Blood"},{"key":"B93","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.mgene.2016.01.001","article-title":"Genetic polymorphisms of interleukin genes and the risk of Alzheimer's disease: An update meta-analysis","volume":"8","author":"Mun","year":"2016","journal-title":"Meta Gene"},{"key":"B94","doi-asserted-by":"publisher","first-page":"2863","DOI":"10.3389\/fimmu.2018.02863","article-title":"Novel PLCG2 mutation in a patient with APLAID and cutis laxa","volume":"9","author":"Neves","year":"2018","journal-title":"Front. Immunol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1080\/15548627.2015.1034406","article-title":"The PRKAA1\/AMPK\u03b11 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML.","volume":"11","author":"Obba","year":"2015","journal-title":"Autophagy"},{"key":"B96","doi-asserted-by":"publisher","first-page":"19842","DOI":"10.1038\/s41598-021-96144-7","article-title":"PLC\u03b32 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages.","volume":"11","author":"Obst","year":"2021","journal-title":"Sci. Rep."},{"key":"B97","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1093\/brain\/awv379","article-title":"Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology","volume":"139","author":"Olmos-Alonso","year":"2016","journal-title":"Brain"},{"key":"B98","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1056\/NEJMoa1102140","article-title":"Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions","volume":"366","author":"Ombrello","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"B99","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1086\/342259","article-title":"Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype","volume":"71","author":"Paloneva","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"B100","doi-asserted-by":"publisher","first-page":"111438","DOI":"10.1016\/j.mad.2021.111438","article-title":"TREM2, microglia, and Alzheimer's disease","volume":"195","author":"Qin","year":"2021","journal-title":"Mech. Ageing Dev."},{"key":"B101","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1182\/blood.2019000854","article-title":"Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: A FILO group study","volume":"134","author":"Quinquenel","year":"2019","journal-title":"Blood"},{"key":"B102","doi-asserted-by":"publisher","first-page":"102181","DOI":"10.1016\/j.pneurobio.2021.102181","article-title":"Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system","volume":"208","author":"Ramirez","year":"2022","journal-title":"Prog. Neurobiol."},{"key":"B103","doi-asserted-by":"publisher","first-page":"123","DOI":"10.2147\/DNND.S228939","article-title":"Alzheimer's disease - why we need early diagnosis","volume":"9","author":"Rasmussen","year":"2019","journal-title":"Degener. Neurol. Neuromuscul. Dis."},{"key":"B104","doi-asserted-by":"publisher","first-page":"5365","DOI":"10.4049\/jimmunol.177.8.5365","article-title":"Differential and nonredundant roles of phospholipase Cgamma2 and phospholipase Cgamma1 in the terminal maturation of NK cells","volume":"177","author":"Regunathan","year":"2006","journal-title":"J. Immunol."},{"key":"B105","doi-asserted-by":"publisher","first-page":"18177","DOI":"10.1074\/jbc.M709715200","article-title":"Phosphorylation regulates tau interactions with Src homology 3 domains of phosphatidylinositol 3-kinase, phospholipase Cgamma1, Grb2, and Src family kinases.","volume":"283","author":"Reynolds","year":"2008","journal-title":"J. Biol. Chem."},{"key":"B106","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1016\/j.biopha.2018.12.133","article-title":"Applications of nanotechnology in drug delivery to the central nervous system","volume":"111","author":"Saeedi","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"B107","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1016\/j.neuron.2018.02.015","article-title":"Tau kinetics in neurons and the human central nervous system","volume":"97","author":"Sato","year":"2018","journal-title":"Neuron"},{"key":"B108","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1111\/neup.12626","article-title":"Aging and Alzheimer's disease pathology","volume":"40","author":"Sengoku","year":"2020","journal-title":"Neuropathology"},{"key":"B109","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.phrs.2008.01.004","article-title":"Expression of amyloid beta peptide in human platelets: Pivotal role of the phospholipase cgamma2-protein kinase C pathway in platelet activation.","volume":"57","author":"Shen","year":"2008","journal-title":"Pharmacol. Res."},{"key":"B110","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1002\/ana.24261","article-title":"Prioritized research recommendations from the national Institute of neurological disorders and stroke Parkinson's disease 2014 conference","volume":"76","author":"Sieber","year":"2014","journal-title":"Ann. Neurol."},{"key":"B111","doi-asserted-by":"publisher","first-page":"e10606","DOI":"10.15252\/emmm.201910606","article-title":"Novel Alzheimer risk genes determine the microglia response to amyloid-beta but not to TAU pathology","volume":"12","author":"Sierksma","year":"2020","journal-title":"EMBO Mol. Med."},{"key":"B112","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1038\/ng.3916","article-title":"Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease","volume":"49","author":"Sims","year":"2017","journal-title":"Nat. Genet."},{"key":"B113","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.jalz.2014.05.1751","article-title":"R47H TREM2 variant increases risk of typical early-onset Alzheimer's disease but not of prion or frontotemporal dementia","volume":"10","author":"Slattery","year":"2014","journal-title":"Alzheimers Dement."},{"key":"B114","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/s13024-018-0244-x","article-title":"Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease","volume":"13","author":"Sosna","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"B115","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/s1471-4914(01)01986-4","article-title":"Clinical application of pharmacogenetics","volume":"7","author":"Spear","year":"2001","journal-title":"Trends Mol. Med."},{"key":"B116","doi-asserted-by":"publisher","first-page":"a021857","DOI":"10.1101\/cshperspect.a021857","article-title":"CSF-1 receptor signaling in myeloid cells","volume":"6","author":"Stanley","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B117","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.bbi.2015.10.010","article-title":"Microglial toll-like receptors and Alzheimer's disease","volume":"52","author":"Su","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"B118","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/s13024-020-00402-7","article-title":"The Alzheimer's disease-associated protective Plc gamma 2-P522R variant promotes immune functions","volume":"15","author":"Takalo","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"B119","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s13073-022-01022-0","article-title":"PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer's disease","volume":"14","author":"Tsai","year":"2022","journal-title":"Genome Med."},{"key":"B120","doi-asserted-by":"publisher","first-page":"104216","DOI":"10.1101\/2020.05.19.104216","article-title":"em>PLCG2<\/em> as a risk factor for Alzheimer\u2019s disease","volume":"2005","author":"Tsai","year":"2020","journal-title":"bioRxiv"},{"key":"B121","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1111\/j.1471-4159.2007.05001.x","article-title":"Toll-like receptors 2 and 4 mediate Abeta(1-42) activation of the innate immune response in a human monocytic cell line","volume":"104","author":"Udan","year":"2008","journal-title":"J. Neurochem."},{"key":"B122","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1007\/s00401-019-02026-8","article-title":"A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity","volume":"138","author":"van der Lee","year":"2019","journal-title":"Acta Neuropathol."},{"key":"B123","doi-asserted-by":"publisher","first-page":"22136","DOI":"10.1074\/jbc.M116.746842","article-title":"The phospholipase C\u03b32 mutants R665W and L845F identified in ibrutinib-resistant chronic lymphocytic leukemia patients are hypersensitive to the rho GTPase Rac2 protein.","volume":"291","author":"Walliser","year":"2016","journal-title":"J. Biol. Chem."},{"key":"B124","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1159\/000110455","article-title":"Role of the toll-like receptor 4 in neuroinflammation in Alzheimer\u2019s disease","volume":"20","author":"Walter","year":"2007","journal-title":"Cell. Physiol. biochem."},{"key":"B125","doi-asserted-by":"publisher","first-page":"ra89","DOI":"10.1126\/scisignal.2005392","article-title":"The autoinhibitory C-terminal SH2 domain of phospholipase C-\u03b32 stabilizes B cell receptor signalosome assembly","volume":"7","author":"Wang","year":"2014","journal-title":"Sci. Signal."},{"key":"B126","doi-asserted-by":"publisher","first-page":"38595","DOI":"10.1074\/jbc.M103675200","article-title":"Four tyrosine residues in phospholipase C-gamma 2, identified as Btk-dependent phosphorylation sites, are required for B cell antigen receptor-coupled calcium signaling","volume":"276","author":"Watanabe","year":"2001","journal-title":"J. Biol. Chem."},{"key":"B127","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1179\/016164105X49436","article-title":"Physicochemical characteristics of soluble oligomeric Abeta and their pathologic role in Alzheimer's disease","volume":"27","author":"Watson","year":"2005","journal-title":"Neurol. Res."},{"key":"B128","doi-asserted-by":"publisher","first-page":"630479","DOI":"10.3389\/fcell.2021.630479","article-title":"Targeting the NLRP3 inflammasome via BTK","volume":"9","author":"Weber","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"B129","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1016\/s0898-6568(01)00191-7","article-title":"Regulation of phospholipase C gamma isoforms in haematopoietic cells: Why one, not the other?","volume":"13","author":"Wilde","year":"2001","journal-title":"Cell. Signal."},{"key":"B130","doi-asserted-by":"publisher","first-page":"2286","DOI":"10.1056\/NEJMoa1400029","article-title":"Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib","volume":"370","author":"Woyach","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"B131","doi-asserted-by":"publisher","first-page":"103586","DOI":"10.1016\/j.dci.2019.103586","article-title":"Regulation and function of macrophage colony-stimulating factor (CSF1) in the chicken immune system","volume":"105","author":"Wu","year":"2020","journal-title":"Dev. Comp. Immunol."},{"key":"B132","doi-asserted-by":"publisher","first-page":"E99","DOI":"10.3390\/cells9010099","article-title":"Csf1 deficiency dysregulates glial responses to demyelination and disturbs CNS white matter remyelination","volume":"9","author":"Wylot","year":"2019","journal-title":"Cells"},{"key":"B133","doi-asserted-by":"publisher","first-page":"rs13","DOI":"10.1126\/scisignal.aaa6711","article-title":"Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases","volume":"8","author":"Xu","year":"2015","journal-title":"Sci. Signal."},{"key":"B134","doi-asserted-by":"publisher","first-page":"7951","DOI":"10.12659\/MSM.916950","article-title":"Effect and mechanism of the Bruton tyrosine kinase (btk) inhibitor ibrutinib on rat model of diabetic foot ulcers","volume":"25","author":"Yang","year":"2019","journal-title":"Med. Sci. Monit."},{"key":"B135","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/j.molmed.2017.03.008","article-title":"TREM2, microglia, and neurodegenerative diseases","volume":"23","author":"Yeh","year":"2017","journal-title":"Trends Mol. Med."},{"key":"B136","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.nurt.2010.07.005","article-title":"Microglial activation in stroke: Therapeutic targets","volume":"7","author":"Yenari","year":"2010","journal-title":"Neurotherapeutics"},{"key":"B137","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/j.immuni.2005.01.018","article-title":"Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry","volume":"22","author":"Yu","year":"2005","journal-title":"Immunity"},{"key":"B138","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1016\/j.cell.2011.09.051","article-title":"CD14 controls the LPS-induced endocytosis of Toll-like receptor 4","volume":"147","author":"Zanoni","year":"2011","journal-title":"Cell"},{"key":"B139","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.brainresbull.2021.02.008","article-title":"Geniposide protects depression through BTK\/JAK2\/STAT1 signaling pathway in lipopolysaccharide-induced depressive mice","volume":"170","author":"Zheng","year":"2021","journal-title":"Brain Res. Bull."},{"key":"B140","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/j.ajhg.2012.08.006","article-title":"A hypermorphic missense mutation in PLCG2, encoding phospholipase C\u03b32, causes a dominantly inherited autoinflammatory disease with immunodeficiency.","volume":"91","author":"Zhou","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"B141","doi-asserted-by":"publisher","first-page":"602508","DOI":"10.3389\/fnins.2020.602508","article-title":"TLR4 targeting as a promising therapeutic strategy for alzheimer disease treatment","volume":"14","author":"Zhou","year":"2020","journal-title":"Front. Neurosci."},{"key":"B142","doi-asserted-by":"publisher","first-page":"5201759","DOI":"10.1155\/2018\/5201759","article-title":"The role of phospholipase C signaling in macrophage-mediated inflammatory response","volume":"2018","author":"Zhu","year":"2018","journal-title":"J. Immunol. Res."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.999061\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T08:01:35Z","timestamp":1662451295000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.999061\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,6]]},"references-count":142,"alternative-id":["10.3389\/fcell.2022.999061"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2022.999061","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,6]]},"article-number":"999061"}}