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While the cell-specific molecular signature of end-stage AD is reasonably well characterized through autopsy material, less is known about the molecular pathways in the human brain involved in the earliest exposure to A\u03b2. Human model systems that not only replicate the pathological features of AD but also the transcriptional landscape in neurons, astrocytes and microglia are crucial for understanding disease mechanisms and for identifying novel therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we used a human 3D iPSC-derived neurosphere model to explore how resident neurons, microglia and astrocytes and their interplay are modified by chronic amyloidosis induced over 3\u20135 weeks by supplementing media with synthetic A\u03b21 -\u200942 oligomers. Neurospheres under chronic A\u03b2 exposure were grown with or without microglia to investigate the functional roles of microglia. Neuronal activity and oxidative stress were monitored using genetically encoded indicators, including GCaMP6f and roGFP1, respectively. Single nuclei RNA sequencing (snRNA-seq) was performed to profile A\u03b2 and microglia driven transcriptional changes in neurons and astrocytes, providing a comprehensive analysis of cellular responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Microglia efficiently phagocytosed A\u03b2 inside neurospheres and significantly reduced neurotoxicity, mitigating amyloidosis-induced oxidative stress and neurodegeneration following different exposure times to A\u03b2. The neuroprotective effects conferred by the presence of microglia was associated with unique gene expression profiles in astrocytes and neurons, including several known AD-associated genes such as\n                      <jats:italic>APOE<\/jats:italic>\n                      . These findings reveal how microglia can directly alter the molecular landscape of AD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our human 3D neurosphere culture system with chronic A\u03b2 exposure reveals how microglia may be essential for the cellular and transcriptional responses in AD pathogenesis. Microglia are not only neuroprotective in neurospheres but also act as key drivers of A\u03b2-dependent\n                      <jats:italic>APOE<\/jats:italic>\n                      expression suggesting critical roles for microglia in regulating\n                      <jats:italic>APOE<\/jats:italic>\n                      in the AD brain. This novel, well characterized, functional in vitro platform offers unique opportunities to study the roles and responses of microglia to A\u03b2 modelling key aspects of human AD. This tool will help identify new therapeutic targets, accelerating the transition from discovery to clinical applications.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-025-03433-3","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T12:07:55Z","timestamp":1745496475000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A 3D human iPSC-derived multi-cell type neurosphere system to model cellular responses to chronic amyloidosis"],"prefix":"10.1186","volume":"22","author":[{"given":"Stefan","family":"Wendt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ada J.","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah N.","family":"Ebert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Declan J.","family":"Brennan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenji","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyang","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da Young","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Sorrentino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Groten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Frew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun B.","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantina","family":"Karamboulas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Delhaye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian R.","family":"Mackenzie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Kaplan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Freda D.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian A.","family":"MacVicar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haakon B.","family":"Nygaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,24]]},"reference":[{"key":"3433_CR1","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1001\/jamaneurol.2013.5847","volume":"71","author":"GS Bloom","year":"2014","unstructured":"Bloom GS. 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