{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:26:59Z","timestamp":1792132019939,"version":"4.4.0"},"reference-count":33,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T00:00:00Z","timestamp":1615248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SNUBH Research Fund","award":["02-2020-006"],"award-info":[{"award-number":["02-2020-006"]}]},{"name":"Basic Science Research Program of the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology","award":["NRF-2018R1D1A1B07050517"],"award-info":[{"award-number":["NRF-2018R1D1A1B07050517"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In this study, we confirmed that the number of resident homeostatic microglia increases during chronic Toxoplasma gondii infection. Given that the progression of Alzheimer\u2019s disease (AD) worsens with the accumulation of amyloid \u03b2 (A\u03b2) plaques, which are eliminated through microglial phagocytosis, we hypothesized that T. gondii-induced microglial proliferation would reduce AD progression. Therefore, we investigated the association between microglial proliferation and A\u03b2 plaque burden using brain tissues isolated from 5XFAD AD mice (AD group) and T. gondii-infected AD mice (AD + Toxo group). In the AD + Toxo group, amyloid plaque burden significantly decreased compared with the AD group; conversely, homeostatic microglial proliferation, and number of plaque-associated microglia significantly increased. As most plaque-associated microglia shifted to the disease-associated microglia (DAM) phenotype in both AD and AD + Toxo groups and underwent apoptosis after the lysosomal degradation of phagocytosed A\u03b2 plaques, this indicates that a sustained supply of homeostatic microglia is required for alleviating A\u03b2 plaque burden. Thus, chronic T. gondii infection can induce microglial proliferation in the brains of mice with progressed AD; a sustained supply of homeostatic microglia is a promising prospect for AD treatment.<\/jats:p>","DOI":"10.3390\/ijms22052764","type":"journal-article","created":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T12:08:01Z","timestamp":1615291681000},"page":"2764","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Reduction of Amyloid Burden by Proliferated Homeostatic Microglia in Toxoplasma gondii-Infected Alzheimer\u2019s Disease Model Mice"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1505-6560","authenticated-orcid":false,"given":"Ji-Hun","family":"Shin","sequence":"first","affiliation":[{"name":"Department of Tropical Medicine and Parasitology, Seoul National University College of Medicine, and Institute of Endemic Diseases, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Sang","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine and Parasitology, Seoul National University College of Medicine, and Institute of Endemic Diseases, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bong-Kwang","family":"Jung","sequence":"additional","affiliation":[{"name":"Institute of Parasitic Diseases, Korea Association of Health Promotion, Seoul 07649, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8645-1966","authenticated-orcid":false,"given":"Seung-Hwan","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine and Parasitology, Seoul National University College of Medicine, and Institute of Endemic Diseases, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Do-Won","family":"Ham","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine and Parasitology, Seoul National University College of Medicine, and Institute of Endemic Diseases, Seoul 03080, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1215-1079","authenticated-orcid":false,"given":"Eun-Hee","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine and Parasitology, Seoul National University College of Medicine, and Institute of Endemic Diseases, Seoul 03080, Korea"},{"name":"Seoul National University Bundang Hospital, Seongnam 13620, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.tcb.2016.02.006","article-title":"Microglia: Architects of the developing nervous system","volume":"26","author":"Frost","year":"2016","journal-title":"Trends. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/jnc.13062","article-title":"Microglia and neuroprotection","volume":"136","author":"Chen","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"790","DOI":"10.3389\/fimmu.2019.00790","article-title":"Phagocytosis in the brain: Homeostasis and disease","volume":"10","author":"Galloway","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1038\/s41593-018-0176-3","article-title":"The mysterious origins of microglia","volume":"21","author":"Ginhoux","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-018-0254-8","article-title":"Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer\u2019s disease","volume":"13","author":"Rangaraju","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1016\/j.cell.2017.05.018","article-title":"A unique microglia type associated with restricting development of Alzheimer\u2019s disease","volume":"169","author":"Spinrad","year":"2017","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/j.cell.2018.05.003","article-title":"Disease-associated microglia: A universal immune sensor of neurodegeneration","volume":"173","author":"Deczkowska","year":"2018","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jung, B.-K., Pyo, K.-H., Shin, K.Y., Hwang, Y.S., Lim, H., Lee, S.J., Moon, J.-H., Lee, S.H., Suh, Y.-H., and Chai, J.-Y. (2012). Toxoplasma gondii infection in the brain inhibits neuronal degeneration and learning and memory impairments in a murine model of Alzheimer\u2019s disease. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033312"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"158","DOI":"10.3389\/fimmu.2018.00158","article-title":"Characteristics of infection immunity regulated by Toxoplasma gondii to maintain chronic infection in the brain","volume":"9","author":"Hwang","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"493","DOI":"10.3389\/fimmu.2020.00493","article-title":"Metabolic reprograming of microglia in the regulation of the innate inflammatory response","volume":"11","author":"Lauro","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"84","DOI":"10.5607\/en.2013.22.2.84","article-title":"An update of animal models of Alzheimer disease with a reevaluation of plaque depositions","volume":"22","author":"Lee","year":"2013","journal-title":"Exp. Neurobiol."},{"key":"ref_12","first-page":"1","article-title":"Chronic Toxoplasma gondii infection enhances \u03b2-amyloid phagocytosis and clearance by recruited monocytes","volume":"4","author":"Israel","year":"2016","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Dong, Y., Li, X., Cheng, J., and Hou, L. (2019). Drug development for Alzheimer\u2019s disease: Microglia induced neuroinflammation as a target?. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030558"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2274","DOI":"10.1002\/glia.23074","article-title":"Microglia contributes to plaque growth by cell death due to uptake of amyloid \u03b2 in the brain of Alzheimer\u2019s disease mouse model","volume":"64","author":"Baik","year":"2016","journal-title":"Glia"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1002\/glia.22988","article-title":"Targeting microglia for the treatment of Alzheimer\u2019s Disease","volume":"64","author":"Wes","year":"2016","journal-title":"Glia"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ham, D.-W., Kim, S.-G., Seo, S.-H., Shin, J.-H., Lee, S.H., and Shin, E.-H. (2020). Chronic Toxoplasma gondii infection alleviates experimental autoimmune encephalomyelitis by the immune regulation inducing reduction in IL-17A\/Th17 via upregulation of SOCS3. Neurotherapeutics, 1\u201318.","DOI":"10.1007\/s13311-020-00957-9"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"159","DOI":"10.31887\/DCNS.2009.11.2\/pdavies","article-title":"Mechanism-based treatments for Alzheimer\u2019s disease","volume":"11","author":"Davies","year":"2009","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"787","DOI":"10.4252\/wjsc.v12.i8.787","article-title":"Stem cell therapy for Alzheimer\u2019s disease","volume":"12","author":"Liu","year":"2020","journal-title":"World J. Stem Cells"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"102149","DOI":"10.1016\/j.nano.2020.102149","article-title":"Novel therapeutic strategies for Alzheimer\u2019s disease: Implications from cell-based therapy and nanotherapy","volume":"24","author":"Derakhshankhah","year":"2020","journal-title":"Nanomedicine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"508","DOI":"10.2174\/1570159X15666170720095240","article-title":"Microglia and astrocytes in Alzheimer\u2019s disease: Implications for therapy","volume":"16","author":"Fakhoury","year":"2018","journal-title":"Curr. Neuropharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"233","DOI":"10.3389\/fnagi.2019.00233","article-title":"Microglia in Alzheimer disease: Well-known targets and new opportunities","volume":"11","author":"Hemonnot","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1186\/s12974-018-1347-6","article-title":"Microglial response to increasing amyloid load saturates with aging: A longitudinal dual tracer in vivo \u03bcPET-study","volume":"15","author":"Blume","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_23","first-page":"1","article-title":"IL-1\u03b2-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia","volume":"16","author":"Pinney","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e20191374","DOI":"10.1084\/jem.20191374","article-title":"Plaque-associated myeloid cells derive from resident microglia in an Alzheimer\u2019s disease model","volume":"217","author":"Croxfordm","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1038\/nn.4631","article-title":"Microglia turnover with aging and in an Alzheimer\u2019s model via long-term in vivo single-cell imaging","volume":"20","author":"Hefendehl","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/0014-4894(91)90070-D","article-title":"Toxoplasma gondii: Blood and tissue kinetics during acute and chronic infections in mice","volume":"73","author":"Derouin","year":"1991","journal-title":"Exp. Parasitol."},{"key":"ref_27","first-page":"1","article-title":"Microglial targets for effective therapies of Alzheimer\u2019s disease","volume":"3","author":"Klegeris","year":"2020","journal-title":"Front. Drug Chem. Clin. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11982","DOI":"10.1523\/JNEUROSCI.3158-09.2009","article-title":"CD14 and toll-like receptors 2 and 4 are required for fibrillar A\u03b2-stimulated microglial activation","volume":"29","author":"Savage","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4283","DOI":"10.1523\/JNEUROSCI.4814-07.2008","article-title":"Dynamics of the microglial\/amyloid interaction indicate a role in plaque maintenance","volume":"28","author":"Bolmont","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3758","DOI":"10.1038\/s41467-019-11674-z","article-title":"Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer\u2019s disease model","volume":"10","author":"Spangenberg","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.conb.2014.02.004","article-title":"Bidirectional tuning of microglia in the developing brain: From neurogenesis to neural circuit formation","volume":"27","author":"Ueno","year":"2014","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1759091417724915","DOI":"10.1177\/1759091417724915","article-title":"Dissecting amyloid beta deposition using distinct strains of the neurotropic parasite Toxoplasma gondii as a novel tool","volume":"9","author":"Cabral","year":"2017","journal-title":"ASN. Neuro"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1161\/ATVBAHA.116.308198","article-title":"Monocyte conversion during inflammation and injury","volume":"37","author":"Kratofil","year":"2017","journal-title":"Arterioscler. Thromb. Vasc. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/5\/2764\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:35:27Z","timestamp":1760160927000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/5\/2764"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,9]]},"references-count":33,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["ijms22052764"],"URL":"https:\/\/doi.org\/10.3390\/ijms22052764","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,9]]}}}