{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T22:04:04Z","timestamp":1789164244677,"version":"build-2803163510"},"reference-count":90,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T00:00:00Z","timestamp":1763769600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T00:00:00Z","timestamp":1763769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Neurobiol"],"published-print":{"date-parts":[[2026,1]]},"DOI":"10.1007\/s12035-025-05293-7","type":"journal-article","created":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T06:54:54Z","timestamp":1763794494000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Brain Organoids in Neurodegenerative Disease Modeling: Advances, Applications and Future Perspectives"],"prefix":"10.1007","volume":"63","author":[{"given":"Wei","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyi","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xulei","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingxing","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongli","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geyu","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihong","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuepu","family":"Pu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4974-4540","authenticated-orcid":false,"given":"Juan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,22]]},"reference":[{"issue":"3","key":"5293_CR1","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1038\/nrd1330","volume":"3","author":"KJ Barnham","year":"2004","unstructured":"Barnham KJ, Masters CL, Bush AI (2004) Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 3(3):205\u2013214","journal-title":"Nat Rev Drug Discov"},{"issue":"7113","key":"5293_CR2","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1038\/nature05292","volume":"443","author":"MT Lin","year":"2006","unstructured":"Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113):787\u2013795","journal-title":"Nature"},{"key":"5293_CR3","doi-asserted-by":"crossref","unstructured":"Hendriks D,\u00a0Pagliaro A, Andreatta F, Ma Z, van Giessen J, Massalini S,\u00a0L\u00f3pez-Iglesias C, van Son GJF\u00a0et al (2024) Human fetal brain self-organizes into long-term expanding organoids[J]. Cell 187(3):712\u2013732","DOI":"10.1016\/j.cell.2023.12.012"},{"issue":"7628","key":"5293_CR4","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1038\/539179a","volume":"539","author":"MT Heemels","year":"2016","unstructured":"Heemels MT (2016) Neurodegenerative diseases[J]. Nature 539(7628):179","journal-title":"Nature"},{"issue":"5","key":"5293_CR5","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.1021\/acs.jmedchem.9b00797","volume":"63","author":"DG Brown","year":"2020","unstructured":"Brown DG, Wobst HJ (2020) Opportunities and challenges in phenotypic screening for neurodegenerative disease research[J]. J Med Chem 63(5):1823\u20131840","journal-title":"J Med Chem"},{"issue":"12","key":"5293_CR6","doi-asserted-by":"publisher","first-page":"2303","DOI":"10.2174\/1570159X20666220830102628","volume":"20","author":"Y Tao","year":"2022","unstructured":"Tao Y, Leng SX, Zhang H (2022) Ketogenic diet: an effective treatment approach for neurodegenerative diseases. Curr Neuropharmacol 20(12):2303\u20132319","journal-title":"Curr Neuropharmacol"},{"key":"5293_CR7","doi-asserted-by":"crossref","unstructured":"Cornblath EJ,\u00a0Robinson JL, Irwin DJ, Lee EB, Lee VM, Trojanowski JQ,\u00a0Bassett DS\u00a0(2020) Defining and predicting transdiagnostic categories of neurodegenerative disease. Nat Biomed Eng 4(8):787\u2013800","DOI":"10.1038\/s41551-020-0593-y"},{"issue":"5","key":"5293_CR8","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1159\/000525639","volume":"56","author":"G Logroscino","year":"2022","unstructured":"Logroscino G, Urso D, Savica R (2022) Descriptive epidemiology of neurodegenerative diseases: what are the critical questions? Neuroepidemiology 56(5):309\u2013318","journal-title":"Neuroepidemiology"},{"key":"5293_CR9","doi-asserted-by":"publisher","unstructured":"Shusharina N,\u00a0Yukhnenko D, Botman S, Sapunov V, Savinov V, Kamyshov G,\u00a0Sayapin D, Voznyuk I\u00a0(2023) Modern methods of diagnostics and treatment of neurodegenerative diseases and depression. Diagnostics. https:\/\/doi.org\/10.3390\/diagnostics13030573","DOI":"10.3390\/diagnostics13030573"},{"key":"5293_CR10","doi-asserted-by":"crossref","unstructured":"Cruz-Vicente P, Passarinha LA, Silvestre S,\u00a0Gallardo E\u00a0(2021) Recent developments in new therapeutic agents against Alzheimer\u2019s and Parkinson\u2019s diseases: in-silico approaches[J]. Molecules 26(8)","DOI":"10.3390\/molecules26082193"},{"key":"5293_CR11","doi-asserted-by":"crossref","unstructured":"Friedman LG, McKeehan N, Hara Y,\u00a0Cummings JL, Matthews DC, Zhu J,\u00a0Mohs RC, Wang D\u00a0et al (2021) Value-generating exploratory trials in neurodegenerative dementias. Neurology 96(20):944\u2013954","DOI":"10.1212\/WNL.0000000000011774"},{"key":"5293_CR12","doi-asserted-by":"crossref","unstructured":"Van Schependom J, D'Haeseleer M (2023) Advances in neurodegenerative diseases[J]. J Clin Med 12(5)","DOI":"10.3390\/jcm12051709"},{"key":"5293_CR13","doi-asserted-by":"crossref","unstructured":"Dutta S, Sklerov M, Teunissen CE, Bitan G (2023) Editorial: trends in biomarkers for neurodegenerative diseases: current research and future perspectives. Front Aging Neurosci 15:1153932","DOI":"10.3389\/fnagi.2023.1153932"},{"issue":"10","key":"5293_CR14","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1038\/s41593-018-0236-8","volume":"21","author":"TM Dawson","year":"2018","unstructured":"Dawson TM, Golde TE, Lagier-Tourenne C (2018) Animal models of neurodegenerative diseases. Nat Neurosci 21(10):1370\u20131379","journal-title":"Nat Neurosci"},{"issue":"1","key":"5293_CR15","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-018-1678-1","volume":"16","author":"P Pound","year":"2018","unstructured":"Pound P, Ritskes-Hoitinga M (2018) Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail. J Transl Med 16(1):304","journal-title":"J Transl Med"},{"key":"5293_CR16","doi-asserted-by":"crossref","unstructured":"Tello JA, Williams HE, Eppler RM,\u00a0Steinhilb ML, Khanna M\u00a0(2022) Animal models of neurodegenerative disease: recent advances in fly highlight innovative approaches to drug discovery. Front Mol Neurosci 15:883358","DOI":"10.3389\/fnmol.2022.883358"},{"key":"5293_CR17","doi-asserted-by":"crossref","unstructured":"Ribitsch I, Baptista PM, Lange-Consiglio A,\u00a0Melotti L, Patruno M, Jenner F,\u00a0Schnabl-Feichter E, Dutton L et al (2020) Large animal models in regenerative medicine and tissue engineering: to do or not to do[J]. Front Bioeng Biotechnol 8:972","DOI":"10.3389\/fbioe.2020.00972"},{"key":"5293_CR18","doi-asserted-by":"crossref","unstructured":"Asahina K, de Bivort BL, Grunwald KI,\u00a0Yapici N (2022) Editorial: revisiting behavioral variability: what it reveals about neural circuit structure and function[J]. Front Behav Neurosci 16:956388","DOI":"10.3389\/fnbeh.2022.956388"},{"key":"5293_CR19","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2014.00211","volume":"8","author":"C Martin","year":"2014","unstructured":"Martin C (2014) Contributions and complexities from the use of in vivo animal models to improve understanding of human neuroimaging signals. Front Neurosci 8:211","journal-title":"Front Neurosci"},{"issue":"11","key":"5293_CR20","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1038\/nm.2224","volume":"16","author":"M Jucker","year":"2010","unstructured":"Jucker M (2010) The benefits and limitations of animal models for translational research in neurodegenerative diseases[J]. Nat Med 16(11):1210\u20131214","journal-title":"Nat Med"},{"issue":"9","key":"5293_CR21","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1007\/s00259-012-2175-z","volume":"39","author":"MI Martic-Kehl","year":"2012","unstructured":"Martic-Kehl MI, Schibli R, Schubiger PA (2012) Can animal data predict human outcome? Problems and pitfalls of translational animal research. Eur J Nucl Med Mol Imaging 39(9):1492\u20131496","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"5293_CR22","doi-asserted-by":"crossref","unstructured":"Mukherjee P, Roy S, Ghosh D, Nandi SK (2022) Role of animal models in biomedical research: a review. Lab Anim Res 38(1):18","DOI":"10.1186\/s42826-022-00128-1"},{"key":"5293_CR23","doi-asserted-by":"crossref","unstructured":"Grimm H, Biller-Andorno N, Buch T,\u00a0Dahlhoff M, Davies G, Cederroth CR,\u00a0Maissen O, Lukas W\u00a0et al (2023) Advancing the 3Rs: innovation, implementation, ethics and society. Front Vet Sci 10:1185706","DOI":"10.3389\/fvets.2023.1185706"},{"key":"5293_CR24","doi-asserted-by":"crossref","unstructured":"Bakken TE, Miller JA, Luo R,\u00a0Bernard A, Bennett JL, Lee CK,\u00a0Bertagnolli D, Parikshak NN\u00a0et al (2015) Spatiotemporal dynamics of the postnatal developing primate brain transcriptome[J]. Hum Mol Genet 24(15):4327\u20134339","DOI":"10.1093\/hmg\/ddv166"},{"key":"5293_CR25","doi-asserted-by":"crossref","unstructured":"Jang H, Kim SH, Koh Y,\u00a0Yoon K-J\u00a0(2022) Engineering brain organoids: toward mature neural circuitry with an intact cytoarchitecture. Int J Stem Cells 15(1):41\u201359","DOI":"10.15283\/ijsc22004"},{"key":"5293_CR26","doi-asserted-by":"crossref","unstructured":"Hogberg HT, Bressler J, Christian KM,\u00a0Harris G, Makri G, O'Driscoll C,\u00a0Pamies D, Smirnova L\u00a0et al (2013) Toward a 3D model of human brain development for studying gene\/environment interactions. Stem Cell Res Ther 4(Suppl 1(Suppl 1)):S4","DOI":"10.1186\/scrt365"},{"key":"5293_CR27","doi-asserted-by":"crossref","unstructured":"Lancaster MA, Renner M, Martin CA,\u00a0Wenzel D, Bicknell LS, Hurles ME,\u00a0Pamies D, Smirnova L\u00a0et al (2013) Cerebral organoids model human brain development and microcephaly. Nature 501(7467):373\u2013379","DOI":"10.1038\/nature12517"},{"key":"5293_CR28","doi-asserted-by":"crossref","unstructured":"Zhang SC, Wernig M, Duncan ID,\u00a0Brustle O, Thomson JA\u00a0(2001) In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol 19(12):1129\u20131133","DOI":"10.1038\/nbt1201-1129"},{"key":"5293_CR29","doi-asserted-by":"crossref","unstructured":"Ying QL, Stavridis M, Griffiths D,\u00a0Li M, Smith A\u00a0(2003) Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture. Nat Biotechnol 21(2):183\u2013186","DOI":"10.1038\/nbt780"},{"key":"5293_CR30","doi-asserted-by":"crossref","unstructured":"Watanabe K, Kamiya D, Nishiyama\u00a0A,\u00a0Katayama T, Nozaki S, Kawasaki H,\u00a0Watanabe Y, Mizuseki K\u00a0et al (2005) Directed differentiation of telencephalic precursors from embryonic stem cells. Nat Neurosci 8(3):288\u2013296","DOI":"10.1038\/nn1402"},{"key":"5293_CR31","doi-asserted-by":"crossref","unstructured":"Gaspard N, Bouschet T, Hourez R,\u00a0Dimidschstein J, Naeije G, van den Ameele J,\u00a0Espuny-Camacho I, Herpoel A\u00a0et al (2008) An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature 455(7211):351\u2013357","DOI":"10.1038\/nature07287"},{"key":"5293_CR32","doi-asserted-by":"crossref","unstructured":"Eiraku M, Watanabe K, Matsuo-Takasaki M,\u00a0Kawada M, Yonemura S, Matsumura M,\u00a0Wataya T, Nishiyama A\u00a0et al (2008) Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3(5):519\u2013532","DOI":"10.1016\/j.stem.2008.09.002"},{"key":"5293_CR33","doi-asserted-by":"crossref","unstructured":"Eiraku M, Takata N, Ishibashi H,\u00a0Kawada M, Sakakura E, Okuda S,\u00a0Sekiguchi K, Adachi T\u00a0et al (2011) Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472(7341):51\u201356","DOI":"10.1038\/nature09941"},{"issue":"10","key":"5293_CR34","doi-asserted-by":"publisher","first-page":"2329","DOI":"10.1038\/nprot.2014.158","volume":"9","author":"MA Lancaster","year":"2014","unstructured":"Lancaster MA, Knoblich JA (2014) Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc 9(10):2329\u20132340","journal-title":"Nat Protoc"},{"key":"5293_CR35","doi-asserted-by":"crossref","unstructured":"Qian X, Nguyen HN, Song MM,\u00a0Hadiono C, Ogden S C, Hammack C,\u00a0Yao B, Hamersky GR\u00a0et al (2016) Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165(5):1238\u20131254","DOI":"10.1016\/j.cell.2016.04.032"},{"key":"5293_CR36","doi-asserted-by":"crossref","unstructured":"Jo J, Xiao Y, Sun AX,\u00a0Cukuroglu E, Tran HD, Goke J,\u00a0Tan ZY, Saw TY\u00a0et al (2016) Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons[J]. Cell Stem Cell 19(2):248\u2013257","DOI":"10.1016\/j.stem.2016.07.005"},{"key":"5293_CR37","doi-asserted-by":"crossref","unstructured":"Muguruma K, Nishiyama A, Kawakami H,\u00a0Hashimoto K, Sasai Y\u00a0(2015) Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep 10(4):537\u2013550","DOI":"10.1016\/j.celrep.2014.12.051"},{"key":"5293_CR38","doi-asserted-by":"crossref","unstructured":"Mariani J, Coppola G, Zhang P,\u00a0Abyzov A, Provini L, Tomasini L,\u00a0Amenduni M, Szekely A\u00a0et al (2015) FOXG1-dependent dysregulation of GABA\/glutamate neuron differentiation in autism spectrum disorders[j]. Cell 162(2):375\u2013390","DOI":"10.1016\/j.cell.2015.06.034"},{"key":"5293_CR39","doi-asserted-by":"crossref","unstructured":"Xiang Y, Tanaka Y, Patterson B,\u00a0Kang Y J, Govindaiah G, Roselaar N,\u00a0Cakir B, Kim K-Y et al (2017) Fusion of regionally specified hPSC-derived organoids models human brain development and interneuron migration[J]. Cell Stem Cell 21(3):383\u2013398","DOI":"10.1016\/j.stem.2017.07.007"},{"key":"5293_CR40","doi-asserted-by":"publisher","unstructured":"Pellegrini L, Bonfio C, Chadwick\u00a0J,\u00a0Begum F, Skehel M, Lancaster MA (2020) Human CNS barrier-forming organoids with cerebrospinal fluid production. Science. https:\/\/doi.org\/10.1126\/science.aaz5626","DOI":"10.1126\/science.aaz5626"},{"issue":"2","key":"5293_CR41","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.102063","volume":"24","author":"J Kim","year":"2021","unstructured":"Kim J, Sullivan GJ, Park IH (2021) How well do brain organoids capture your brain? iScience 24(2):102063","journal-title":"iScience"},{"issue":"Suppl 1","key":"5293_CR42","doi-asserted-by":"publisher","DOI":"10.1186\/2193-1801-4-S1-L49","volume":"4","author":"E Arenas","year":"2015","unstructured":"Arenas E, Salto C, Villaescusa C (2015) WNT signaling in midbrain dopaminergic neuron development and cell replacement therapies for Parkinson\u2019s disease. Springerplus 4(Suppl 1):L49","journal-title":"Springerplus"},{"key":"5293_CR43","doi-asserted-by":"crossref","unstructured":"Chambers SM, Fasano CA, Papapetrou EP,\u00a0Tomishima M, Sadelain M, Studer L\u00a0(2009) Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 27(3):275\u2013280","DOI":"10.1038\/nbt.1529"},{"key":"5293_CR44","doi-asserted-by":"crossref","unstructured":"Kadoshima T, Sakaguchi H, Nakano T,\u00a0Soen M, Ando S, Eiraku M,\u00a0Sasai Y\u00a0(2013) Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci USA 110(50):20284\u201320289","DOI":"10.1073\/pnas.1315710110"},{"key":"5293_CR45","doi-asserted-by":"crossref","unstructured":"Rosebrock D, Arora S, Mutukula N,\u00a0Volkman R, Gralinska E, Balaskas A,\u00a0Hern\u00e1ndez AA, Buschow R\u00a0et al (2022) Enhanced cortical neural stem cell identity through short SMAD and WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells. Nat Cell Biol 24(6):981\u2013995","DOI":"10.1038\/s41556-022-00929-5"},{"key":"5293_CR46","doi-asserted-by":"crossref","unstructured":"Lee SM, Tole S, Grove E,\u00a0McMahon AP\u00a0(2000) A local Wnt-3a signal is required for development of the mammalian hippocampus[J]. Development 127(3):457\u2013467","DOI":"10.1242\/dev.127.3.457"},{"key":"5293_CR47","doi-asserted-by":"crossref","unstructured":"Kim DS, Lee JS, Leem JW,\u00a0Huh YJ, Kim JY, Kim HS,\u00a0Park I-H, Daley GQ et al (2010) Robust enhancement of neural differentiation from human ES and iPS cells regardless of their innate difference in differentiation propensity[J]. Stem Cell Rev Rep 6(2):270\u2013281","DOI":"10.1007\/s12015-010-9138-1"},{"key":"5293_CR48","doi-asserted-by":"crossref","unstructured":"Velasco S, Kedaigle AJ, Simmons SK,\u00a0Nash A, Rocha M, Quadrato G,\u00a0Paulsen B, Nguyen L et al (2019) Individual brain organoids reproducibly form cell diversity of the human cerebral cortex[J]. Nature 570(7762):523\u2013527","DOI":"10.1038\/s41586-019-1289-x"},{"issue":"1","key":"5293_CR49","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1038\/s41418-020-0566-4","volume":"28","author":"J Sidhaye","year":"2021","unstructured":"Sidhaye J, Knoblich JA (2021) Brain organoids: an ensemble of bioassays to investigate human neurodevelopment and disease. Cell Death Differ 28(1):52\u201367","journal-title":"Cell Death Differ"},{"issue":"3","key":"5293_CR50","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1038\/s41582-020-00435-y","volume":"17","author":"F Leng","year":"2021","unstructured":"Leng F, Edison P (2021) Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol 17(3):157\u2013172","journal-title":"Nat Rev Neurol"},{"key":"5293_CR51","doi-asserted-by":"crossref","unstructured":"Raja WK, Mungenast AE, Lin YT,\u00a0Ko T, Abdurrob F, Seo J,\u00a0Tsai L-H\u00a0(2016) Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulates Alzheimer\u2019s disease phenotypes. PLoS One 11(9):e161969","DOI":"10.1371\/journal.pone.0161969"},{"key":"5293_CR52","doi-asserted-by":"crossref","unstructured":"Choi SH, Kim YH, Hebisch M,\u00a0Sliwinski C, Lee S, D'Avanzo C,\u00a0Chen H, Hooli B\u00a0et al (2014) A three-dimensional human neural cell culture model of Alzheimer\u2019s disease. Nature 515(7526):274\u2013278","DOI":"10.1038\/nature13800"},{"key":"5293_CR53","doi-asserted-by":"crossref","unstructured":"Gonzalez C, Armijo E, Bravo-Alegria J,\u00a0Becerra-Calixto A, Mays CE, Soto C\u00a0(2018) Modeling amyloid beta and tau pathology in human cerebral organoids. Mol Psychiatry 23(12):2363\u20132374","DOI":"10.1038\/s41380-018-0229-8"},{"key":"5293_CR54","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.semcdb.2020.05.012","volume":"111","author":"S Wray","year":"2021","unstructured":"Wray S (2021) Modelling neurodegenerative disease using brain organoids. Semin Cell Dev Biol 111:60\u201366","journal-title":"Semin Cell Dev Biol"},{"key":"5293_CR55","doi-asserted-by":"crossref","unstructured":"Yan Y, Song L, Bejoy J,\u00a0Zhao J, Kanekiyo T, Bu G,\u00a0Zhou Y, Li Y\u00a0(2018) Modeling neurodegenerative microenvironment using cortical organoids derived from human stem cells. Tissue Eng Part A 24(13\u201314):1125\u20131137","DOI":"10.1089\/ten.tea.2017.0423"},{"key":"5293_CR56","doi-asserted-by":"crossref","unstructured":"Kuehner JN, Chen J, Bruggeman EC,\u00a0Wang F, Li Y, Xu C, McEachin ZT, Li Z\u00a0et al (2021) 5-hydroxymethylcytosine is dynamically regulated during forebrain organoid development and aberrantly altered in Alzheimer\u2019s disease. Cell Rep 35(4):109042","DOI":"10.1016\/j.celrep.2021.109042"},{"key":"5293_CR57","doi-asserted-by":"crossref","unstructured":"Sreenivasamurthy S, Laul M, Zhao N,\u00a0Kim T, Zhu D\u00a0(2023) Current progress of cerebral organoids for modeling Alzheimer\u2019s disease origins and mechanisms. Bioeng Transl Med 8(2):e10378","DOI":"10.1002\/btm2.10378"},{"key":"5293_CR58","doi-asserted-by":"crossref","unstructured":"Mamun AA, Uddin MS, Bin BM,\u00a0Zaman S, Begum Y, Bulbul IJ, Islam MS, Sarwar MS\u00a0et al (2020) Molecular insight into the therapeutic promise of targeting APOE4 for Alzheimer\u2019s disease[J]. Oxid Med Cell Longev 2020:5086250","DOI":"10.1155\/2020\/5086250"},{"key":"5293_CR59","doi-asserted-by":"crossref","unstructured":"Lin YT, Seo J, Gao F,\u00a0Feldman HM, Wen HL, Penney J, Cam HP, Gjoneska E\u00a0et al (2018) APOE4 causes widespread molecular and cellular alterations associated with Alzheimer\u2019s disease phenotypes in human iPSC-derived brain cell types[J]. Neuron 98(6):1141\u20131154","DOI":"10.1016\/j.neuron.2018.05.008"},{"key":"5293_CR60","doi-asserted-by":"crossref","unstructured":"Zhao J, Fu Y, Yamazaki Y,\u00a0Ren Y, Davis MD, Liu CC, Lu W, Wang X\u00a0et al (2021) Author correction: APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer\u2019s disease patient iPSC-derived cerebral organoids[J]. Nat Commun 12(1):2707","DOI":"10.1038\/s41467-021-23081-4"},{"key":"5293_CR61","doi-asserted-by":"crossref","unstructured":"Chen X, Sun G, Tian E,\u00a0Zhang M, Davtyan H, Beach TG, Reiman EM, Blurton-Jones M\u00a0et al (2021) Modeling sporadic Alzheimer\u2019s disease in human brain organoids under serum exposure. Adv Sci 8(18):e2101462","DOI":"10.1002\/advs.202101462"},{"key":"5293_CR62","doi-asserted-by":"crossref","unstructured":"Chang Y, Kim J, Park H, Choi H, Kim J\u00a0(2020) Modelling neurodegenerative diseases with 3D brain organoids. Biol Rev Camb Philos Soc 95(5):1497\u20131509","DOI":"10.1111\/brv.12626"},{"key":"5293_CR63","doi-asserted-by":"crossref","unstructured":"Jo J, Yang L, Tran HD,\u00a0Yu W, Sun AX, Chang YY, Jung BC, Lee SJ\u00a0et al (2021) Lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and alpha-synuclein mutations[J]. Ann Neurol 90(3):490\u2013505","DOI":"10.1002\/ana.26166"},{"key":"5293_CR64","doi-asserted-by":"crossref","unstructured":"Kim H, Park HJ, Choi H,\u00a0Chang Y, Park H, Shin J, Kim J, Lengner CJ\u00a0et al (2019) Modeling G2019S-LRRK2 sporadic Parkinson\u2019s disease in 3D midbrain organoids[j]. Stem Cell Rep 12(3):518\u2013531","DOI":"10.1016\/j.stemcr.2019.01.020"},{"key":"5293_CR65","doi-asserted-by":"crossref","unstructured":"Smits LM, Reinhardt L, Reinhardt P,\u00a0Glatza M, Monzel AS, Stanslowsky N,\u00a0Rosato-Siri MD, Zanon A et al (2019) Modeling Parkinson\u2019s disease in midbrain-like organoids. NPJ Parkinsons Dis 5:5","DOI":"10.1038\/s41531-019-0078-4"},{"key":"5293_CR66","doi-asserted-by":"crossref","unstructured":"Chlebanowska P, Tejchman A, Sulkowski M,\u00a0Skrzypek K, Majka M\u00a0(2020) Use of 3D Organoids as a model to study idiopathic form of Parkinson\u2019s disease[J]. Int J Mol Sci 21(3)","DOI":"10.3390\/ijms21030694"},{"key":"5293_CR67","doi-asserted-by":"crossref","unstructured":"Jarazo J, Barmpa K, Modamio J,\u00a0Saraiva C, Sabate-Soler S, Rosety I,\u00a0Griesbeck A, Skwirblies F\u00a0et al (2022) Parkinson\u2019s disease phenotypes in patient neuronal cultures and brain organoids improved by 2-hydroxypropyl-beta-cyclodextrin treatment[J]. Mov Disord 37(1):80\u201394","DOI":"10.1002\/mds.28810"},{"issue":"9557","key":"5293_CR68","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/S0140-6736(07)60111-1","volume":"369","author":"FO Walker","year":"2007","unstructured":"Walker FO (2007) Huntington\u2019s disease. Lancet 369(9557):218\u2013228","journal-title":"Lancet"},{"key":"5293_CR69","doi-asserted-by":"crossref","unstructured":"Kawada J, Kaneda S, Kirihara T,\u00a0Maroof A, Levi T, Eggan K, Fujii T, Ikeuchi Y\u00a0(2017) Generation of a motor nerve organoid with human stem cell-derived neurons. Stem Cell Reports 9(5):1441\u20131449","DOI":"10.1016\/j.stemcr.2017.09.021"},{"key":"5293_CR70","doi-asserted-by":"crossref","unstructured":"Conforti P, Besusso D, Bocchi VD,\u00a0Faedo A, Cesana E, Rossetti G, Ranzani V, Svendsen CN\u00a0et al (2018) Faulty neuronal determination and cell polarization are reverted by modulating HD early phenotypes. Proc Natl Acad Sci U S A 115(4):E762\u2013E771","DOI":"10.1073\/pnas.1715865115"},{"key":"5293_CR71","doi-asserted-by":"crossref","unstructured":"Jo M, Lee S, Jeon YM,\u00a0Kim S, Kwon Y, Kim HJ\u00a0(2020) The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies. Exp Mol Med 52(10):1652\u20131662","DOI":"10.1038\/s12276-020-00513-7"},{"key":"5293_CR72","doi-asserted-by":"crossref","unstructured":"Szebenyi K, Wenger L, Sun Y,\u00a0Dunn AWE, Limegrover CA, Gibbons GM, Conci E, Paulsen O\u00a0et al (2021) Human ALS\/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology. Nat Neurosci 24(11):1542\u20131554","DOI":"10.1038\/s41593-021-00923-4"},{"key":"5293_CR73","doi-asserted-by":"crossref","unstructured":"Faustino MJ, Fischer C, Urzi A,\u00a0Vidal R, Kunz S, Ruffault PL,\u00a0Kabuss L, Hube I et al (2020) Self-organizing 3D human trunk neuromuscular organoids[J]. Cell Stem Cell 27(3):498","DOI":"10.1016\/j.stem.2020.08.011"},{"key":"5293_CR74","doi-asserted-by":"crossref","unstructured":"Hong Y, Dong X, Chang L,\u00a0Xie C, Chang M, Aguilar JS, Lin J, Lin J\u00a0et al (2023) Microglia-containing cerebral organoids derived from induced pluripotent stem cells for the study of neurological diseases. iScience 26(3):106267","DOI":"10.1016\/j.isci.2023.106267"},{"key":"5293_CR75","doi-asserted-by":"crossref","unstructured":"Hruska-Plochan M, Wiersma VI, Betz KM,\u00a0Mallona I, Ronchi S, Maniecka Z, Hock EM, Tantardini E et al (2024) A model of human neural networks reveals NPTX2 pathology in ALS and FTLD. Nature 626(8001):1073\u20131083","DOI":"10.1038\/s41586-024-07042-7"},{"key":"5293_CR76","doi-asserted-by":"crossref","unstructured":"Pereira JD, DuBreuil DM, Devlin AC,\u00a0Held A, Sapir Y, Berezovski E, Hawrot J, Dorfman K\u00a0et al (2021) Human sensorimotor organoids derived from healthy and amyotrophic lateral sclerosis stem cells form neuromuscular junctions[J]. Nat Commun 12(1):4744","DOI":"10.1038\/s41467-021-24776-4"},{"key":"5293_CR77","doi-asserted-by":"crossref","unstructured":"Kim HJ, Raphael AR, LaDow ES,\u00a0McGurk L, Weber RA, Trojanowski JQ, Lee VM, Finkbeiner S et al (2014) Therapeutic modulation of eIF2alpha phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models[J]. Nat Genet 46(2):152\u2013160","DOI":"10.1038\/ng.2853"},{"key":"5293_CR78","doi-asserted-by":"crossref","unstructured":"Noh MY, Kwon HS, Kwon MS,\u00a0Nahm M, Jin HK, Bae JS, Kim SH (2025) Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions. Mol Neurodegener 20(1):82","DOI":"10.1186\/s13024-025-00867-4"},{"issue":"21","key":"5293_CR79","doi-asserted-by":"publisher","first-page":"3444","DOI":"10.1016\/j.neuron.2022.10.004","volume":"110","author":"B Cakir","year":"2022","unstructured":"Cakir B, Kiral FR, Park IH (2022) Advanced in vitro models: microglia in action. Neuron 110(21):3444\u20133457","journal-title":"Neuron"},{"key":"5293_CR80","doi-asserted-by":"crossref","unstructured":"Kistemaker L, van Bodegraven EJ, de Vries HE,\u00a0Hol EM\u00a0(2025) Vascularized human brain organoids: current possibilities and prospects[J]. Trends Biotechnol 43(6):1275\u20131285","DOI":"10.1016\/j.tibtech.2024.11.021"},{"key":"5293_CR81","doi-asserted-by":"crossref","unstructured":"Stoberl N, Maguire E, Salis EM,\u00a0Shaw B, Hall-Roberts H\u00a0(2023) Human iPSC-derived glia models for the study of neuroinflammation. J Neuroinflammation 20(1):231","DOI":"10.1186\/s12974-023-02919-2"},{"key":"5293_CR82","doi-asserted-by":"crossref","unstructured":"Kumar S, Reynolds K, Ji Y,\u00a0Gu R, Rai S, Zhou CJ\u00a0(2019) Impaired neurodevelopmental pathways in autism spectrum disorder: a review of signaling mechanisms and crosstalk[J]. J Neurodev Disord 11(1):10","DOI":"10.1186\/s11689-019-9268-y"},{"key":"5293_CR83","doi-asserted-by":"crossref","unstructured":"Tsai TY, Sikora M, Xia P,\u00a0Colak-Champollion T, Knaut H, Heisenberg CP, Megason SG\u00a0(2020) An adhesion code ensures robust pattern formation during tissue morphogenesis. Science 370(6512):113\u2013116","DOI":"10.1126\/science.aba6637"},{"key":"5293_CR84","doi-asserted-by":"crossref","unstructured":"Hergenreder E, Minotti AP, Zorina Y,\u00a0Oberst P, Zhao Z, Munguba H, Calder EL, Baggiolini A\u00a0(2024) Author correction: combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons. Nat Biotechnol 42(10):1615","DOI":"10.1038\/s41587-024-02233-z"},{"issue":"1","key":"5293_CR85","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1146\/annurev-bioeng-103023-122327","volume":"27","author":"F Andreatta","year":"2025","unstructured":"Andreatta F, Hendriks D, Artegiani B (2025) Human organoids as an emerging tool for genome screenings. Annu Rev Biomed Eng 27(1):157\u2013183","journal-title":"Annu Rev Biomed Eng"},{"key":"5293_CR86","doi-asserted-by":"crossref","unstructured":"Urenda JP, Del DA, Birtele M,\u00a0Quadrato G\u00a0(2023) Present and future modeling of human psychiatric connectopathies with brain organoids[J]. Biol Psychiatry 93(7):606\u2013615","DOI":"10.1016\/j.biopsych.2022.12.017"},{"key":"5293_CR87","doi-asserted-by":"crossref","unstructured":"Horns F, Martinez JA, Fan C,\u00a0Haque M, Linton JM, Tobin V, Santat L, Maggiolo AO et al (2023) Engineering RNA export for measurement and manipulation of living cells[J]. Cell 186(17):3642\u20133658","DOI":"10.1016\/j.cell.2023.06.013"},{"key":"5293_CR88","doi-asserted-by":"crossref","unstructured":"Morales PI, Smirnova L, Muotri AR,\u00a0Wahlin KJ, Kahn J, Boyd JL, Gracias DH, Harris TD\u00a0et al (2023) First organoid intelligence (OI) workshop to form an OI community[J]. Front Artif Intell 6:1116870","DOI":"10.3389\/frai.2023.1116870"},{"issue":"2","key":"5293_CR89","doi-asserted-by":"publisher","first-page":"191","DOI":"10.14573\/altex.2303261","volume":"40","author":"L Smirnova","year":"2023","unstructured":"Smirnova L, Morales PI, Hartung T (2023) Organoid intelligence (OI) - the ultimate functionality of a brain microphysiological system. ALTEX 40(2):191\u2013203","journal-title":"ALTEX"},{"key":"5293_CR90","doi-asserted-by":"crossref","unstructured":"Pantoja I, Ding L, Leite P,\u00a0Marques SA, Romero JC, Alam El Din DM, Zack DJ, Chamling X\u00a0(2023) A novel approach to increase glial cell populations in brain microphysiological systems[J]. bioRxiv\u00a0","DOI":"10.1101\/2023.09.14.557775"}],"container-title":["Molecular Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-025-05293-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12035-025-05293-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-025-05293-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T19:03:59Z","timestamp":1763838239000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12035-025-05293-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,22]]},"references-count":90,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["5293"],"URL":"https:\/\/doi.org\/10.1007\/s12035-025-05293-7","relation":{},"ISSN":["0893-7648","1559-1182"],"issn-type":[{"value":"0893-7648","type":"print"},{"value":"1559-1182","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,22]]},"assertion":[{"value":"25 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"142"}}