{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:39:31Z","timestamp":1792643971082,"version":"4.5.0"},"reference-count":128,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100005205","name":"Janssen Research and Development","doi-asserted-by":"publisher","award":["TMC114FD2HTX4008"],"award-info":[{"award-number":["TMC114FD2HTX4008"]}],"id":[{"id":"10.13039\/100005205","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J of Neuroscience"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Two\u2010dimensional (2D) cell culture systems and conventional animal models have been crucial in the study of central nervous system (CNS) pathology. However, they are limited in their abilities to elucidate human\u2010specific neurobiology and disease etiology. Human induced pluripotent stem cell (iPSC)\u2010derived brain organoids have emerged as a complementary platform that offers a three\u2010dimensional (3D) structure and human\u2010specific environment. They exhibit cellular heterogeneity, apical\u2013basal polarity, and the ability to perform tissue\u2010specific functions such as absorption, secretion, and electrophysiological activity. This review critically evaluates the use of iPSC\u2010derived brain organoids as a disease\u2010focused approach to study neuroinflammation, neurodegeneration, infection, and aging. Organoids provide a model for early pathogenic events, cellular interactions, and human\u2010specific responses, providing insights into disease hallmarks such as tau and amyloid pathology, the vulnerability of dopaminergic neurons, and host\u2013pathogen interactions. However, they are limited by developmental immaturity, inadequate systemic integration, and heterogeneity across models, which hinders their ability to represent late\u2010stage disease progression and human level physiology. Therefore, their primary use lies in modeling human\u2010specific early disease mechanisms, while integration with animal models and in\u00a0vitro systems is crucial for progressing translational neuroscience.<\/jats:p>","DOI":"10.1111\/ejn.70687","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T01:25:55Z","timestamp":1789435555000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Human iPSC\u2010Derived Brain Organoids: A Disease\u2010Oriented Evaluation of Modeling Fidelity"],"prefix":"10.1111","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5605-4997","authenticated-orcid":false,"given":"Bishwa R.","family":"Pokharel","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology Brody School of Medicine at East Carolina University  Greenville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Dickerson","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Brody School of Medicine at East Carolina University  Greenville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjana G.","family":"Shenoy","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Brody School of Medicine at East Carolina University  Greenville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mira S.","family":"Ramasamy","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Brody School of Medicine at East Carolina University  Greenville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niska","family":"Majumdar","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Brody School of Medicine at East Carolina University  Greenville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul P.","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Brody School of Medicine at East Carolina University  Greenville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7990-7307","authenticated-orcid":false,"given":"Shaw M.","family":"Akula","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Brody School of Medicine at East Carolina University  Greenville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bios.2023.115635"},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000095"},{"key":"e_1_2_15_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44319-025-00619-x"},{"key":"e_1_2_15_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat6720"},{"key":"e_1_2_15_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-111020-090812"},{"key":"e_1_2_15_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.683459"},{"key":"e_1_2_15_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4304"},{"key":"e_1_2_15_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-024-03024-8"},{"key":"e_1_2_15_10_1","doi-asserted-by":"publisher","DOI":"10.4062\/biomolther.2020.175"},{"key":"e_1_2_15_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-18815-8"},{"key":"e_1_2_15_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.640212"},{"key":"e_1_2_15_13_1","doi-asserted-by":"publisher","DOI":"10.1088\/1758-5090\/ad4c08"},{"key":"e_1_2_15_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2024.11.008"},{"key":"e_1_2_15_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.836480"},{"key":"e_1_2_15_16_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.310671"},{"key":"e_1_2_15_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28043-y"},{"key":"e_1_2_15_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202202936"},{"key":"e_1_2_15_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202303444"},{"key":"e_1_2_15_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2020.103568"},{"key":"e_1_2_15_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-022-00951-5"},{"key":"e_1_2_15_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2019.09.002"},{"key":"e_1_2_15_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202403952"},{"key":"e_1_2_15_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-016-0139-7"},{"key":"e_1_2_15_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.06.051"},{"key":"e_1_2_15_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2022.101636"},{"key":"e_1_2_15_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106230"},{"key":"e_1_2_15_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.03.018"},{"key":"e_1_2_15_29_1","doi-asserted-by":"publisher","DOI":"10.3390\/v14030634"},{"key":"e_1_2_15_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-023-00368-8"},{"key":"e_1_2_15_31_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00036.2016"},{"key":"e_1_2_15_32_1","doi-asserted-by":"publisher","DOI":"10.1089\/adt.2014.573"},{"key":"e_1_2_15_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-022-00723-9"},{"key":"e_1_2_15_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-025-04660-4"},{"key":"e_1_2_15_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11010124"},{"key":"e_1_2_15_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2019.12.007"},{"key":"e_1_2_15_37_1","article-title":"Cerebral Organoids With Integrated Endothelial Networks Emulate the Neurovascular Unit and Mitigate Core Necrosis","volume":"12","author":"Fumado Navarro J.","year":"2025","journal-title":"Advancement of Science"},{"key":"e_1_2_15_38_1","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202101340"},{"key":"e_1_2_15_39_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.708389"},{"key":"e_1_2_15_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2024.07.008"},{"key":"e_1_2_15_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.nanolett.7b04982"},{"key":"e_1_2_15_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241814387"},{"key":"e_1_2_15_43_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201709054"},{"key":"e_1_2_15_44_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom15081118"},{"key":"e_1_2_15_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2021.04.006"},{"key":"e_1_2_15_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2020.146653"},{"key":"e_1_2_15_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09151-3"},{"key":"e_1_2_15_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2021.101333"},{"key":"e_1_2_15_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1654-9"},{"key":"e_1_2_15_50_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.201120"},{"key":"e_1_2_15_51_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells14161278"},{"key":"e_1_2_15_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-0259-3"},{"key":"e_1_2_15_53_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241512528"},{"key":"e_1_2_15_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibtech.2024.11.021"},{"key":"e_1_2_15_55_1","article-title":"Multi\u2010Region Brain Organoids Integrating Cerebral, Mid\u2010Hindbrain, and Endothelial Systems","volume":"12","author":"Kshirsagar A.","year":"2025","journal-title":"Advancement of Science"},{"key":"e_1_2_15_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12517"},{"key":"e_1_2_15_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2025.03.042"},{"key":"e_1_2_15_58_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-017-0362-8"},{"key":"e_1_2_15_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2024.10.002"},{"key":"e_1_2_15_60_1","first-page":"1","article-title":"Human Disease Models in Drug Development","volume":"11","author":"Loewa A.","year":"2023","journal-title":"Nature Reviews Bioengineering"},{"key":"e_1_2_15_61_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells14241986"},{"key":"e_1_2_15_62_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2021.691136"},{"key":"e_1_2_15_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibtech.2025.02.009"},{"key":"e_1_2_15_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2025.102632"},{"key":"e_1_2_15_65_1","doi-asserted-by":"publisher","DOI":"10.1177\/02611929231157756"},{"key":"e_1_2_15_66_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241511902"},{"key":"e_1_2_15_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-021-00632-z"},{"key":"e_1_2_15_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.105680"},{"key":"e_1_2_15_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2018.02.010"},{"key":"e_1_2_15_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2017.03.010"},{"key":"e_1_2_15_71_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25063148"},{"key":"e_1_2_15_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.12.051"},{"key":"e_1_2_15_73_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-023-03302-x"},{"key":"e_1_2_15_74_1","doi-asserted-by":"publisher","DOI":"10.1002\/ame2.12487"},{"key":"e_1_2_15_75_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa268"},{"key":"e_1_2_15_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2024.09.017"},{"key":"e_1_2_15_77_1","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.2430"},{"key":"e_1_2_15_78_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-023-00402-4"},{"key":"e_1_2_15_79_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2025.102753"},{"key":"e_1_2_15_80_1","doi-asserted-by":"crossref","unstructured":"Pantula A. B.Zhou I. E.Morales Pantoja et\u00a0al.2025. \u201cComputational Modeling of Necrosis in Neural Organoids.\u201d bioRxiv: the preprint server for biology.","DOI":"10.1101\/2025.04.30.651571"},{"key":"e_1_2_15_81_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2025.1515340"},{"key":"e_1_2_15_82_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz5626"},{"key":"e_1_2_15_83_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.768108"},{"key":"e_1_2_15_84_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.671734"},{"key":"e_1_2_15_85_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46004-5"},{"key":"e_1_2_15_86_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.140707"},{"key":"e_1_2_15_87_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-021-00496-y"},{"key":"e_1_2_15_88_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2024.114753"},{"key":"e_1_2_15_89_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24167"},{"key":"e_1_2_15_90_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells12030420"},{"key":"e_1_2_15_91_1","first-page":"3483","article-title":"Pros and Cons of Human Brain Organoids to Study Alzheimer's Disease","volume":"16","author":"Sainz A.","year":"2024","journal-title":"Aging and Disease"},{"key":"e_1_2_15_92_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9896"},{"key":"e_1_2_15_93_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23105404"},{"key":"e_1_2_15_94_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2023.1248727"},{"key":"e_1_2_15_95_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.07.050"},{"key":"e_1_2_15_96_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1538920"},{"key":"e_1_2_15_97_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2025.04.006"},{"key":"e_1_2_15_98_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1222878110"},{"key":"e_1_2_15_99_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2023.1281581"},{"key":"e_1_2_15_100_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adj4735"},{"key":"e_1_2_15_101_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells14141074"},{"key":"e_1_2_15_102_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-020-0566-4"},{"key":"e_1_2_15_103_1","doi-asserted-by":"publisher","DOI":"10.1002\/ddr.70121"},{"key":"e_1_2_15_104_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-018-0032-7"},{"key":"e_1_2_15_105_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13062-023-00360-2"},{"key":"e_1_2_15_106_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202302745"},{"key":"e_1_2_15_107_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.00359"},{"key":"e_1_2_15_108_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26020620"},{"key":"e_1_2_15_109_1","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.70161"},{"key":"e_1_2_15_110_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-023-02919-2"},{"key":"e_1_2_15_111_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.76707"},{"key":"e_1_2_15_112_1","doi-asserted-by":"publisher","DOI":"10.15283\/ijsc22006"},{"key":"e_1_2_15_113_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2019.08.002"},{"key":"e_1_2_15_114_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2024.1419526"},{"key":"e_1_2_15_115_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1289-x"},{"key":"e_1_2_15_116_1","doi-asserted-by":"publisher","DOI":"10.1042\/ETLS20210245"},{"key":"e_1_2_15_117_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2025.10.006"},{"key":"e_1_2_15_118_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-48452-5"},{"key":"e_1_2_15_119_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40164-018-0122-9"},{"key":"e_1_2_15_120_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-025-02253-4"},{"key":"e_1_2_15_121_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70406"},{"key":"e_1_2_15_122_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2022.872794"},{"key":"e_1_2_15_123_1","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2021.54.10.094"},{"key":"e_1_2_15_124_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2025.1634582"},{"key":"e_1_2_15_125_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.872134"},{"key":"e_1_2_15_126_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01892-1"},{"key":"e_1_2_15_127_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-025-02308-7"},{"key":"e_1_2_15_128_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2024.1351734"},{"key":"e_1_2_15_129_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-024-00712-0"}],"container-title":["European Journal of Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ejn.70687","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/ejn.70687","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ejn.70687","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T03:55:08Z","timestamp":1792641308000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/ejn.70687"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9]]},"references-count":128,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1111\/ejn.70687"],"URL":"https:\/\/doi.org\/10.1111\/ejn.70687","archive":["Portico"],"relation":{},"ISSN":["0953-816X","1460-9568"],"issn-type":[{"value":"0953-816X","type":"print"},{"value":"1460-9568","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9]]},"assertion":[{"value":"2026-07-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70687"}}