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

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.