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Here we developed a Neural Microglia Integrated Multicellular iPSC-derived Cultured Spheroids (NeuroMIMICS) system that enables measurements of both neural network activity and immune responses using human iPSC-derived microglia, astrocytes, and neurons. We validated microglia functionalities in these neural tri-cultures including phagocytic activity, directed motility, and inflammatory responses. RNAseq analysis revealed a phenotypical acquisition of immune functionality via microglia incorporation, supported by increased cytokine production in spheroids challenged with pathogen-like insults. We then demonstrated that the incorporation of healthy microglia corrected alpha-synuclein A53T-mediated dysfunctional phenotypes in the neural spheroids. This work demonstrates a unique immunocompetent functional neural model that is robust and suited for high-throughput screening, laying the groundwork for its application to accelerate the discovery of new therapeutics for neurological diseases.<\/jats:p>","DOI":"10.1038\/s42003-026-10696-w","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T11:55:26Z","timestamp":1784116526000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Microglia integrated neural spheroids enable neuroinflammatory responses and correct network dysfunction induced by alpha-synuclein mutation"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7918-1040","authenticated-orcid":false,"given":"Jiajing","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3965-4381","authenticated-orcid":false,"given":"Yi Wei","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica","family":"Medina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yining Irene","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Carrasco Carvajal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4569-9137","authenticated-orcid":false,"given":"Marc","family":"Ferrer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8451-978X","authenticated-orcid":false,"given":"Emily M.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"10696_CR1","doi-asserted-by":"publisher","first-page":"e52728","DOI":"10.1371\/journal.pone.0052728","volume":"7","author":"K Hua","year":"2012","unstructured":"Hua, K., Schindler, M. 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