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Microglial activation is an early event in PD and may play a key role in pathological \u03b1Syn aggregation and transmission, as well as in clearance of \u03b1Syn and immunotherapy efficacy. Our aim was to investigate how different proposed mechanisms of anti\u2010\u03b1Syn immunotherapy may contribute to pathology reduction in various PD\u2010like mouse models. Our mechanistic model of PD pathology in mouse includes \u03b1Syn production, aggregation, degradation and distribution in neurons, secretion into interstitial fluid, internalization, and subsequent clearance by neurons and microglia. It describes the influence of neuroinflammation on PD pathogenesis and dopaminergic neurodegeneration. Multiple data from mouse PD models were used for calibration and validation. Simulations of anti\u2010\u03b1Syn passive immunotherapy adequately reproduce preclinical data and suggest that (1) immunotherapy is efficient in the reduction of aggregated \u03b1Syn in various models of PD\u2010like pathology; (2) prevention of aSyn spread only does not reduce the pathology; (3) a decrease in microglial inflammatory activation and aSyn aggregation may be alternative therapy approaches in PD\u2010like pathology.<\/jats:p>","DOI":"10.1002\/psp4.13223","type":"journal-article","created":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T11:32:59Z","timestamp":1724412779000},"page":"1798-1809","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Quantitative systems pharmacology model of \u03b1\u2010synuclein pathology in Parkinson's disease\u2010like mouse for investigation of passive immunotherapy mechanisms"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2972-4794","authenticated-orcid":false,"given":"Olga","family":"Ivanova","sequence":"first","affiliation":[{"name":"InSysBio CY  Limassol Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4643-3023","authenticated-orcid":false,"given":"Tatiana","family":"Karelina","sequence":"additional","affiliation":[{"name":"InSysBio CY  Limassol Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,8,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0329-1"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80886-7"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-20-08797.2002"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2017.75"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201566"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2202867"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2203395"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(02)00065-9"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2009.08.001"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.04.013"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22094994"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-16-06309.2000"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9071687"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12362"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0069146"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mbs.2016.05.002"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s41109-020-00307-w"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1088\/1478-3975\/ac8516"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-41382-0"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12868-017-0341-8"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2017.05.002"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0022225"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2018.10.016"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-016-0072-9"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2019.104582"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnint.2021.715190"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23970"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa090"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1907-y"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0019338"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.04-2751com"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-019-09641-8"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0123162"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-8-44"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awu213"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5314-13.2014"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25767-1"}],"container-title":["CPT: Pharmacometrics &amp; 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