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Peer-reviewedCC BY 4.0ACS Chemical Neuroscience

Conditional Mutant MAPT Overexpression in Neural Organoids Elicits Robust Tau Accumulation and Pathological Transcriptomic Responses

  • Andrew Kjar1
  • Hyosung Kim2
  • Madeline R. Spetz1
  • Zev Jarrett3
  • Melanie Fernandez1
  • Jaime Wang1
  • Maria L. Russotti1
  • Caroline Bodnya4
  • Daniel Chavarria2
  • Timothy J. Hohman5
  • Vivian Gama4,6,7
  • Brad Grueter3,8,9
2 more authors
  • Jonathan M. Brunger1,6,10
  • Ethan S. Lippmann1,2,6
10 affiliations
  1. 1Department of Biomedical Engineering, Vanderbilt University, Nashville 37235-1631, Tennessee, United States
  2. 2Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville 37235-1631, Tennessee, United States
  3. 3Department of Pharmacology, Vanderbilt University, Nashville 37235-1631, Tennessee, United States
  4. 4Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville 37232, Tennessee, United States
  5. 5Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical Center, Nashville 37232-2102, Tennessee, United States
  6. 6Vanderbilt Brain Institute, Vanderbilt University, Nashville 37235-1631, Tennessee, United States
  7. 7Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville 37235-1631, Tennessee, United States
  8. 8Department of Anesthesiology, Vanderbilt University Medical Center, Nashville 37235-1631, Tennessee, United States
  9. 9Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville 37235-1631, Tennessee, United States
  10. 10Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville 37232-2102, Tennessee, United States
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Abstract

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 MAPT, which encodes the microtubule-associated protein tau that is implicated in tauopathies. Induction of mutant MAPT 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.

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Cite

BibTeXRIS
BibTeX
@article{kjar2026conditional,
  title = {{Conditional Mutant MAPT Overexpression in Neural Organoids Elicits Robust Tau Accumulation and Pathological Transcriptomic Responses}},
  author = {Andrew Kjar and Hyosung Kim and Madeline R. Spetz and Zev Jarrett and Melanie Fernandez and Jaime Wang and Maria L. Russotti and Caroline Bodnya and Daniel Chavarria and Timothy J. Hohman and Vivian Gama and Brad Grueter and Jonathan M. Brunger and Ethan S. Lippmann},
  journal = {ACS Chemical Neuroscience},
  year = {2026},
  month = sep,
  doi = {10.1021/acschemneuro.6c00376},
  url = {https://doi.org/10.1021/acschemneuro.6c00376},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Conditional Mutant MAPT Overexpression in Neural Organoids Elicits Robust Tau Accumulation and Pathological Transcriptomic Responses
AU  - Andrew Kjar
AU  - Hyosung Kim
AU  - Madeline R. Spetz
AU  - Zev Jarrett
AU  - Melanie Fernandez
AU  - Jaime Wang
AU  - Maria L. Russotti
AU  - Caroline Bodnya
AU  - Daniel Chavarria
AU  - Timothy J. Hohman
AU  - Vivian Gama
AU  - Brad Grueter
AU  - Jonathan M. Brunger
AU  - Ethan S. Lippmann
PY  - 2026
DA  - 2026/09/28
JO  - ACS Chemical Neuroscience
DO  - 10.1021/acschemneuro.6c00376
UR  - https://doi.org/10.1021/acschemneuro.6c00376
AB  - 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 MAPT, which encodes the microtubule-associated protein tau that is implicated in tauopathies. Induction of mutant MAPT 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.
SN  - 1948-7193
ER  -