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oai:figshare.com:article/34018850 2026-09-29T01:05:53Z category_12 category_13 category_14 category_15 category_19 category_61 category_122 portal_63 item_type_6 month_year_09_2026

Conditional Mutant MAPT Overexpression in Neural Organoids Elicits Robust Tau Accumulation and Pathological Transcriptomic Responses Andrew Kjar (21252584) Hyosung Kim (3079212) Madeline R. Spetz (19774488) Zev Jarrett (25133639) Melanie Fernandez (25133642) Jaime Wang (25133645) Maria L. Russotti (25133648) Caroline Bodnya (10291730) Daniel Chavarria (1641433) Timothy J. Hohman (8356254) Vivian Gama (10291742) Brad Grueter (25133651) Jonathan M. Brunger (13841415) Ethan S. Lippmann (1915207) Cell Biology Genetics Molecular Biology Neuroscience Pharmacology Developmental Biology Mental Health via doxycycline treatment neural organoids presents neural organoid systems measured transcriptomic responses lines containing disease concept framework showing inducible expression cassettes associated protein tau mapt </ italic mapt </ phosphorylated tau inducible mutant taken together relevant alleles potential complement pathological events neurodegenerative phenotypes like regions like pathology generally relied cortical plate Modeling neurodegenerative conditions in neural organoids presents a potential complement to existing preclinical translation pipelines. Prior neural organoid models have generally relied on human induced pluripotent stem cell (iPSC) lines containing disease-relevant alleles. However, this strategy limits temporal control over the initiation and progression of pathological events. In this study, we provide a proof-of-concept framework showing that neurodegenerative phenotypes can be triggered by inducible expression cassettes. We developed an iPSC line harboring doxycycline-inducible mutant <i>MAPT</i>, which encodes the microtubule-associated protein tau that is implicated in tauopathies. Induction of mutant <i>MAPT</i> via doxycycline treatment in differentiating neural organoids yielded accumulation of phosphorylated tau, which localized inside individual neuron somas within the cortical plate-like regions. Importantly, measured transcriptomic responses to tau overexpression bore key similarities to human clinical transcriptomic data. Taken together, we present an approach for controlling the initiation and progression of proteinopathy-like pathology in neural organoid systems. 2026-09-28T00:00:00Z Text Journal contribution 10.1021/acschemneuro.6c00376.s002 https://figshare.com/articles/journal_contribution/Conditional_Mutant_MAPT_Overexpression_in_Neural_Organoids_Elicits_Robust_Tau_Accumulation_and_Pathological_Transcriptomic_Responses/34018850 CC BY-NC 4.0