{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:28:41Z","timestamp":1791808121365,"version":"4.3.4"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,1,13]],"date-time":"2017-01-13T00:00:00Z","timestamp":1484265600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,1,13]],"date-time":"2017-01-13T00:00:00Z","timestamp":1484265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Sandhoff disease (SD) is caused by the loss of \u03b2-hexosaminidase (Hex) enzymatic activity in lysosomes resulting from <jats:italic>Hexb<\/jats:italic> mutations. In SD patients, the Hex substrate GM2 ganglioside accumulates abnormally in neuronal cells, resulting in neuronal loss, microglial activation, and astrogliosis. <jats:italic>Hexb<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice, which manifest a phenotype similar to SD, serve as animal models for examining the pathophysiology of SD. <jats:italic>Hexb<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice reach ~8 weeks without obvious neurological defects; however, trembling begins at 12 weeks and is accompanied by startle reactions and increased limb tone. These symptoms gradually become severe by 16\u201318 weeks. Immune reactions caused by autoantibodies have been recently associated with the pathology of SD. The inhibition of immune activation may represent a novel therapeutic target for SD. Herein, SD mice (<jats:italic>Hexb<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) were crossed to mice lacking an activating immune receptor (<jats:italic>FcR\u03b3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) to elucidate the potential relationship between immune responses activated through SD autoantibodies and astrogliosis. Microglial activation and astrogliosis were observed in cortices of <jats:italic>Hexb<\/jats:italic><jats:sup><jats:italic>\u2212<\/jats:italic>\/<jats:italic>\u2212<\/jats:italic><\/jats:sup> mice during the asymptomatic phase, and were inhibited in <jats:italic>Hexb<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><jats:italic>FcR\u03b3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. Moreover, early astrogliosis and impaired motor coordination in <jats:italic>Hexb<\/jats:italic><jats:sup><jats:italic>\u2212<\/jats:italic>\/<jats:italic>\u2212<\/jats:italic><\/jats:sup> mice could be ameliorated by immunosuppressants, such as FTY720. Our findings demonstrate the importance of early treatment and the therapeutic effectiveness of immunosuppression in SD.<\/jats:p>","DOI":"10.1038\/srep40518","type":"journal-article","created":{"date-parts":[[2017,1,13]],"date-time":"2017-01-13T10:09:17Z","timestamp":1484302157000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["FcR\u03b3-dependent immune activation initiates astrogliosis during the asymptomatic phase of Sandhoff disease model mice"],"prefix":"10.1038","volume":"7","author":[{"given":"Yasuhiro","family":"Ogawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Sano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Irisa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kodama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiri","family":"Furusawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsutoshi","family":"Kaizu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Yanagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Tsukimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadayasu","family":"Togawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoji","family":"Yamanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohji","family":"Itoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Sakuraba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiko","family":"Oishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,1,13]]},"reference":[{"key":"BFsrep40518_CR1","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1006\/geno.1994.1318","volume":"21","author":"S Yamanaka","year":"1994","unstructured":"Yamanaka, S., Johnson, O. N., Norflus, F., Boles, D. J. & Proia, R. L. Structure and expression of the mouse beta-hexosaminidase genes, Hexa and Hexb. Genomics 21, 588\u2013596, doi: 10.1006\/geno.1994.1318 (1994).","journal-title":"Genomics"},{"key":"BFsrep40518_CR2","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1038\/ng1095-170","volume":"11","author":"K Sango","year":"1995","unstructured":"Sango, K. et al. Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism. Nature genetics 11, 170\u2013176, doi: 10.1038\/ng1095-170 (1995).","journal-title":"Nature genetics"},{"key":"BFsrep40518_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/hmg\/5.1.1","volume":"5","author":"D Phaneuf","year":"1996","unstructured":"Phaneuf, D. et al. Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases. Human molecular genetics 5, 1\u201314 (1996).","journal-title":"Human molecular genetics"},{"key":"BFsrep40518_CR4","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1038\/ng1196-348","volume":"14","author":"K Sango","year":"1996","unstructured":"Sango, K. et al. Mice lacking both subunits of lysosomal beta-hexosaminidase display gangliosidosis and mucopolysaccharidosis. Nature genetics 14, 348\u2013352, doi: 10.1038\/ng1196-348 (1996).","journal-title":"Nature genetics"},{"key":"BFsrep40518_CR5","unstructured":"Volk, B. W. Pathologic anatomy 36\u201367 (Grune and Stratton, Inc., 1964)."},{"key":"BFsrep40518_CR6","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1093\/hmg\/6.11.1879","volume":"6","author":"JQ Huang","year":"1997","unstructured":"Huang, J. Q. et al. Apoptotic cell death in mouse models of GM2 gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases. Human molecular genetics 6, 1879\u20131885 (1997).","journal-title":"Human molecular genetics"},{"key":"BFsrep40518_CR7","doi-asserted-by":"publisher","first-page":"4371","DOI":"10.1093\/hmg\/ddr364","volume":"20","author":"TJ Sargeant","year":"2011","unstructured":"Sargeant, T. J. et al. Adeno-associated virus-mediated expression of beta-hexosaminidase prevents neuronal loss in the Sandhoff mouse brain. Human molecular genetics 20, 4371\u20134380, doi: 10.1093\/hmg\/ddr364 (2011).","journal-title":"Human molecular genetics"},{"key":"BFsrep40518_CR8","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1172\/JCI19639","volume":"113","author":"A Yamaguchi","year":"2004","unstructured":"Yamaguchi, A. et al. Possible role of autoantibodies in the pathophysiology of GM2 gangliosidoses. The Journal of clinical investigation 113, 200\u2013208, doi: 10.1172\/JCI19639 (2004).","journal-title":"The Journal of clinical investigation"},{"key":"BFsrep40518_CR9","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1093\/brain\/awg089","volume":"126","author":"M Jeyakumar","year":"2003","unstructured":"Jeyakumar, M. et al. Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain 126, 974\u2013987 (2003).","journal-title":"Brain"},{"key":"BFsrep40518_CR10","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1002\/ana.20242","volume":"56","author":"M Jeyakumar","year":"2004","unstructured":"Jeyakumar, M. et al. NSAIDs increase survival in the Sandhoff disease mouse: synergy with N-butyldeoxynojirimycin. Annals of neurology 56, 642\u2013649, doi: 10.1002\/ana.20242 (2004).","journal-title":"Annals of neurology"},{"key":"BFsrep40518_CR11","doi-asserted-by":"publisher","first-page":"8425","DOI":"10.1073\/pnas.0400625101","volume":"101","author":"YP Wu","year":"2004","unstructured":"Wu, Y. P. & Proia, R. L. Deletion of macrophage-inflammatory protein 1 alpha retards neurodegeneration in Sandhoff disease mice. Proceedings of the National Academy of Sciences of the United States of America 101, 8425\u20138430, doi: 10.1073\/pnas.0400625101 (2004).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"BFsrep40518_CR12","doi-asserted-by":"publisher","first-page":"10954","DOI":"10.1073\/pnas.97.20.10954","volume":"97","author":"R Wada","year":"2000","unstructured":"Wada, R., Tifft, C. J. & Proia, R. L. Microglial activation precedes acute neurodegeneration in Sandhoff disease and is suppressed by bone marrow transplantation. Proceedings of the National Academy of Sciences of the United States of America 97, 10954\u201310959 (2000).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"BFsrep40518_CR13","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1038\/nn1997","volume":"10","author":"UK Hanisch","year":"2007","unstructured":"Hanisch, U. K. & Kettenmann, H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nature neuroscience 10, 1387\u20131394, doi: 10.1038\/nn1997 (2007).","journal-title":"Nature neuroscience"},{"key":"BFsrep40518_CR14","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.pneurobio.2005.06.004","volume":"76","author":"ML Block","year":"2005","unstructured":"Block, M. L. & Hong, J. S. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Progress in neurobiology 76, 77\u201398, doi: 10.1016\/j.pneurobio.2005.06.004 (2005).","journal-title":"Progress in neurobiology"},{"key":"BFsrep40518_CR15","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1016\/S0166-2236(97)01139-9","volume":"20","author":"JL Ridet","year":"1997","unstructured":"Ridet, J. L., Malhotra, S. K., Privat, A. & Gage, F. H. Reactive astrocytes: cellular and molecular cues to biological function. Trends in neurosciences 20, 570\u2013577 (1997).","journal-title":"Trends in neurosciences"},{"key":"BFsrep40518_CR16","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s00401-009-0619-8","volume":"119","author":"MV Sofroniew","year":"2010","unstructured":"Sofroniew, M. V. & Vinters, H. V. Astrocytes: biology and pathology. Acta neuropathologica 119, 7\u201335, doi: 10.1007\/s00401-009-0619-8 (2010).","journal-title":"Acta neuropathologica"},{"key":"BFsrep40518_CR17","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.brainres.2006.10.057","volume":"1129","author":"C Rohl","year":"2007","unstructured":"Rohl, C., Lucius, R. & Sievers, J. The effect of activated microglia on astrogliosis parameters in astrocyte cultures. Brain research 1129, 43\u201352, doi: 10.1016\/j.brainres.2006.10.057 (2007).","journal-title":"Brain research"},{"key":"BFsrep40518_CR18","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/1743-8454-4-5","volume":"4","author":"JM Miller","year":"2007","unstructured":"Miller, J. M. & McAllister, J. P. 2nd Reduction of astrogliosis and microgliosis by cerebrospinal fluid shunting in experimental hydrocephalus. Cerebrospinal Fluid Res 4, 5, doi: 10.1186\/1743-8454-4-5 (2007).","journal-title":"Cerebrospinal Fluid Res"},{"key":"BFsrep40518_CR19","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1007\/s12035-010-8098-4","volume":"41","author":"D Zhang","year":"2010","unstructured":"Zhang, D., Hu, X., Qian, L., O\u2019Callaghan, J. P. & Hong, J. S. Astrogliosis in CNS pathologies: is there a role for microglia? Mol Neurobiol 41, 232\u2013241, doi: 10.1007\/s12035-010-8098-4 (2010).","journal-title":"Mol Neurobiol"},{"key":"BFsrep40518_CR20","first-page":"269","volume":"19","author":"M Aschner","year":"1998","unstructured":"Aschner, M. Astrocytes as mediators of immune and inflammatory responses in the CNS. Neurotoxicology 19, 269\u2013281 (1998).","journal-title":"Neurotoxicology"},{"key":"BFsrep40518_CR21","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1146\/annurev.neuro.22.1.219","volume":"22","author":"F Gonzalez-Scarano","year":"1999","unstructured":"Gonzalez-Scarano, F. & Baltuch, G. Microglia as mediators of inflammatory and degenerative diseases. Annual review of neuroscience 22, 219\u2013240, doi: 10.1146\/annurev.neuro.22.1.219 (1999).","journal-title":"Annual review of neuroscience"},{"key":"BFsrep40518_CR22","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1016\/S0301-0082(98)00069-0","volume":"57","author":"WJ Streit","year":"1999","unstructured":"Streit, W. J., Walter, S. A. & Pennell, N. A. Reactive microgliosis. Progress in neurobiology 57, 563\u2013581 (1999).","journal-title":"Progress in neurobiology"},{"key":"BFsrep40518_CR23","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/nri2206","volume":"8","author":"F Nimmerjahn","year":"2008","unstructured":"Nimmerjahn, F. & Ravetch, J. V. Fcgamma receptors as regulators of immune responses. Nature reviews. Immunology 8, 34\u201347, doi: 10.1038\/nri2206 (2008).","journal-title":"Nature reviews. Immunology"},{"key":"BFsrep40518_CR24","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1007\/s12017-009-8099-5","volume":"12","author":"E Okun","year":"2010","unstructured":"Okun, E., Mattson, M. P. & Arumugam, T. V. Involvement of Fc receptors in disorders of the central nervous system. Neuromolecular Med 12, 164\u2013178, doi: 10.1007\/s12017-009-8099-5 (2010).","journal-title":"Neuromolecular Med"},{"key":"BFsrep40518_CR25","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1038\/nri856","volume":"2","author":"T Takai","year":"2002","unstructured":"Takai, T. Roles of Fc receptors in autoimmunity. Nature reviews. Immunology 2, 580\u2013592, doi: 10.1038\/nri856 (2002).","journal-title":"Nature reviews. Immunology"},{"key":"BFsrep40518_CR26","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/0092-8674(94)90115-5","volume":"76","author":"T Takai","year":"1994","unstructured":"Takai, T., Li, M., Sylvestre, D., Clynes, R. & Ravetch, J. V. FcR gamma chain deletion results in pleiotrophic effector cell defects. Cell 76, 519\u2013529 (1994).","journal-title":"Cell"},{"key":"BFsrep40518_CR27","doi-asserted-by":"publisher","first-page":"4930","DOI":"10.1523\/JNEUROSCI.5480-05.2006","volume":"26","author":"S Brahmachari","year":"2006","unstructured":"Brahmachari, S., Fung, Y. K. & Pahan, K. Induction of glial fibrillary acidic protein expression in astrocytes by nitric oxide. The Journal of neuroscience: the official journal of the Society for Neuroscience 26, 4930\u20134939, doi: 10.1523\/JNEUROSCI.5480-05.2006 (2006).","journal-title":"The Journal of neuroscience: the official journal of the Society for Neuroscience"},{"key":"BFsrep40518_CR28","doi-asserted-by":"publisher","first-page":"e51155","DOI":"10.1371\/journal.pone.0051155","volume":"7","author":"E Fujita-Jimbo","year":"2012","unstructured":"Fujita-Jimbo, E. et al. Mutation in Parkinson disease-associated, G-protein-coupled receptor 37 (GPR37\/PaelR) is related to autism spectrum disorder. PloS one 7, e51155, doi: 10.1371\/journal.pone.0051155 (2012).","journal-title":"PloS one"},{"key":"BFsrep40518_CR29","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1515\/REVNEURO.2007.18.2.137","volume":"18","author":"C Gemma","year":"2007","unstructured":"Gemma, C. & Bickford, P. C. Interleukin-1beta and caspase-1: players in the regulation of age-related cognitive dysfunction. Rev Neurosci 18, 137\u2013148 (2007).","journal-title":"Rev Neurosci"},{"key":"BFsrep40518_CR30","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1016\/j.molcel.2014.10.019","volume":"56","author":"S Mir","year":"2014","unstructured":"Mir, S., Sen, T. & Sen, N. Cytokine-induced GAPDH sulfhydration affects PSD95 degradation and memory. Mol Cell 56, 786\u2013795, doi: 10.1016\/j.molcel.2014.10.019 (2014).","journal-title":"Mol Cell"},{"key":"BFsrep40518_CR31","doi-asserted-by":"publisher","first-page":"3960","DOI":"10.1093\/hmg\/ddt250","volume":"22","author":"H Abo-Ouf","year":"2013","unstructured":"Abo-Ouf, H. et al. Deletion of tumor necrosis factor-alpha ameliorates neurodegeneration in Sandhoff disease mice. Human molecular genetics 22, 3960\u20133975, doi: 10.1093\/hmg\/ddt250 (2013).","journal-title":"Human molecular genetics"},{"key":"BFsrep40518_CR32","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.molbrainres.2004.10.026","volume":"133","author":"S Kyrkanides","year":"2005","unstructured":"Kyrkanides, S., Miller, J. H., Brouxhon, S. M., Olschowka, J. A. & Federoff, H. J. beta-hexosaminidase lentiviral vectors: transfer into the CNS via systemic administration. Brain research. Molecular brain research 133, 286\u2013298, doi: 10.1016\/j.molbrainres.2004.10.026 (2005).","journal-title":"Brain research. Molecular brain research"},{"key":"BFsrep40518_CR33","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1124\/mol.64.5.1199","volume":"64","author":"SD Sorensen","year":"2003","unstructured":"Sorensen, S. D. et al. Common signaling pathways link activation of murine PAR-1, LPA, and S1P receptors to proliferation of astrocytes. Mol Pharmacol 64, 1199\u20131209, doi: 10.1124\/mol.64.5.1199 (2003).","journal-title":"Mol Pharmacol"},{"key":"BFsrep40518_CR34","doi-asserted-by":"publisher","first-page":"2257","DOI":"10.1093\/hmg\/ddn126","volume":"17","author":"YP Wu","year":"2008","unstructured":"Wu, Y. P., Mizugishi, K., Bektas, M., Sandhoff, R. & Proia, R. L. Sphingosine kinase 1\/S1P receptor signaling axis controls glial proliferation in mice with Sandhoff disease. Human molecular genetics 17, 2257\u20132264, doi: 10.1093\/hmg\/ddn126 (2008).","journal-title":"Human molecular genetics"},{"key":"BFsrep40518_CR35","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1634\/stemcells.2006-0223","volume":"25","author":"A Kimura","year":"2007","unstructured":"Kimura, A. et al. Essential roles of sphingosine 1-phosphate\/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury. Stem cells 25, 115\u2013124, doi: 10.1634\/stemcells.2006-0223 (2007).","journal-title":"Stem cells"},{"key":"BFsrep40518_CR36","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.bbrc.2009.08.142","volume":"389","author":"B Czech","year":"2009","unstructured":"Czech, B. et al. The immunomodulatory sphingosine 1-phosphate analog FTY720 reduces lesion size and improves neurological outcome in a mouse model of cerebral ischemia. Biochemical and biophysical research communications 389, 251\u2013256, doi: 10.1016\/j.bbrc.2009.08.142 (2009).","journal-title":"Biochemical and biophysical research communications"},{"key":"BFsrep40518_CR37","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1186\/1742-2094-8-76","volume":"8","author":"SJ Jackson","year":"2011","unstructured":"Jackson, S. J., Giovannoni, G. & Baker, D. Fingolimod modulates microglial activation to augment markers of remyelination. J Neuroinflammation 8, 76, doi: 10.1186\/1742-2094-8-76 (2011).","journal-title":"J Neuroinflammation"},{"key":"BFsrep40518_CR38","doi-asserted-by":"publisher","first-page":"15769","DOI":"10.1073\/pnas.95.26.15769","volume":"95","author":"J Yrjanheikki","year":"1998","unstructured":"Yrjanheikki, J., Keinanen, R., Pellikka, M., Hokfelt, T. & Koistinaho, J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proceedings of the National Academy of Sciences of the United States of America 95, 15769\u201315774 (1998).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"BFsrep40518_CR39","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1038\/77528","volume":"6","author":"M Chen","year":"2000","unstructured":"Chen, M. et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nature medicine 6, 797\u2013801, doi: 10.1038\/77528 (2000).","journal-title":"Nature medicine"},{"key":"BFsrep40518_CR40","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1227\/00006123-200106000-00051","volume":"48","author":"RO Sanchez Mejia","year":"2001","unstructured":"Sanchez Mejia, R. O., Ona, V. O., Li, M. & Friedlander, R. M. Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery 48, 1393\u20131399, discussion 1399\u20131401 (2001).","journal-title":"Neurosurgery"},{"key":"BFsrep40518_CR41","doi-asserted-by":"publisher","first-page":"1763","DOI":"10.1523\/JNEUROSCI.22-05-01763.2002","volume":"22","author":"DC Wu","year":"2002","unstructured":"Wu, D. C. et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. The Journal of neuroscience: the official journal of the Society for Neuroscience 22, 1763\u20131771 (2002).","journal-title":"The Journal of neuroscience: the official journal of the Society for Neuroscience"},{"key":"BFsrep40518_CR42","doi-asserted-by":"publisher","first-page":"14669","DOI":"10.1073\/pnas.251341998","volume":"98","author":"Y Du","year":"2001","unstructured":"Du, Y. et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson\u2019s disease. Proceedings of the National Academy of Sciences of the United States of America 98, 14669\u201314674, doi: 10.1073\/pnas.251341998 (2001).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"BFsrep40518_CR43","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.2174\/1568026033451880","volume":"3","author":"BG Gold","year":"2003","unstructured":"Gold, B. G. & Villafranca, J. E. Neuroimmunophilin ligands: the development of novel neuroregenerative\/neuroprotective compounds. Curr Top Med Chem 3, 1368\u20131375 (2003).","journal-title":"Curr Top Med Chem"},{"key":"BFsrep40518_CR44","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1111\/j.1582-4934.2004.tb00259.x","volume":"8","author":"B Kaminska","year":"2004","unstructured":"Kaminska, B., Gaweda-Walerych, K. & Zawadzka, M. Molecular mechanisms of neuroprotective action of immunosuppressants\u2013facts and hypotheses. J Cell Mol Med 8, 45\u201358 (2004).","journal-title":"J Cell Mol Med"},{"key":"BFsrep40518_CR45","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1038\/sj.jcbfm.9600064","volume":"25","author":"MR Macleod","year":"2005","unstructured":"Macleod, M. R., O\u2019Collins, T., Horky, L. L., Howells, D. W. & Donnan, G. A. Systematic review and metaanalysis of the efficacy of FK506 in experimental stroke. J Cereb Blood Flow Metab 25, 713\u2013721, doi: 10.1038\/sj.jcbfm.9600064 (2005).","journal-title":"J Cereb Blood Flow Metab"},{"key":"BFsrep40518_CR46","doi-asserted-by":"publisher","first-page":"1442","DOI":"10.1001\/archneurol.2010.191","volume":"67","author":"JM Plane","year":"2010","unstructured":"Plane, J. M., Shen, Y., Pleasure, D. E. & Deng, W. Prospects for minocycline neuroprotection. Archives of neurology 67, 1442\u20131448, doi: 10.1001\/archneurol.2010.191 (2010).","journal-title":"Archives of neurology"},{"key":"BFsrep40518_CR47","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.1007\/s00109-012-0925-9","volume":"90","author":"M Zawadzka","year":"2012","unstructured":"Zawadzka, M. et al. Early steps of microglial activation are directly affected by neuroprotectant FK506 in both in vitro inflammation and in rat model of stroke. J Mol Med (Berl) 90, 1459\u20131471, doi: 10.1007\/s00109-012-0925-9 (2012).","journal-title":"J Mol Med (Berl)"},{"key":"BFsrep40518_CR48","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1124\/jpet.102.045658","volume":"305","author":"M Fujino","year":"2003","unstructured":"Fujino, M. et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J Pharmacol Exp Ther 305, 70\u201377, doi: 10.1124\/jpet.102.045658 (2003).","journal-title":"J Pharmacol Exp Ther"},{"key":"BFsrep40518_CR49","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.1523\/JNEUROSCI.1619-13.2014","volume":"34","author":"Y Shigemoto-Mogami","year":"2014","unstructured":"Shigemoto-Mogami, Y., Hoshikawa, K., Goldman, J. E., Sekino, Y. & Sato, K. Microglia enhance neurogenesis and oligodendrogenesis in the early postnatal subventricular zone. The Journal of neuroscience: the official journal of the Society for Neuroscience 34, 2231\u20132243, doi: 10.1523\/JNEUROSCI.1619-13.2014 (2014).","journal-title":"The Journal of neuroscience: the official journal of the Society for Neuroscience"},{"key":"BFsrep40518_CR50","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1006\/exnr.1999.7119","volume":"158","author":"S Bavetta","year":"1999","unstructured":"Bavetta, S., Hamlyn, P. J., Burnstock, G., Lieberman, A. R. & Anderson, P. N. The effects of FK506 on dorsal column axons following spinal cord injury in adult rats: neuroprotection and local regeneration. Experimental neurology 158, 382\u2013393, doi: 10.1006\/exnr.1999.7119 (1999).","journal-title":"Experimental neurology"},{"key":"BFsrep40518_CR51","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1177\/0192623310385254","volume":"39","author":"M Sidoryk-Wegrzynowicz","year":"2011","unstructured":"Sidoryk-Wegrzynowicz, M., Wegrzynowicz, M., Lee, E., Bowman, A. B. & Aschner, M. Role of astrocytes in brain function and disease. Toxicologic pathology 39, 115\u2013123, doi: 10.1177\/0192623310385254 (2011).","journal-title":"Toxicologic pathology"},{"key":"BFsrep40518_CR52","first-page":"180","volume":"53","author":"AC Christy","year":"2014","unstructured":"Christy, A. C., Byrnes, K. R. & Settle, T. L. Evaluation of medicated gel as a supplement to providing acetaminophen in the drinking water of C57BL\/6 mice after surgery. J Am Assoc Lab Anim Sci 53, 180\u2013184 (2014).","journal-title":"J Am Assoc Lab Anim Sci"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep40518.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep40518","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep40518.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T22:08:36Z","timestamp":1671833316000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep40518"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,13]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,2,6]]}},"alternative-id":["BFsrep40518"],"URL":"https:\/\/doi.org\/10.1038\/srep40518","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,13]]},"assertion":[{"value":"2 April 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 December 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 January 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"40518"}}