Humanized tauopathy chimeras uncover microglial and lncRNA strategies for neuroprotection

Qu, W.; Fan, L.; Jang, M. W.; Ye, P.; Cordes, E.; Aikedan, A.; Hu, W.; Nagiri, R. K.; Wong, M. Y.; Luo, W.; Blurton-Jones, M.; Tilgner, H. U.; Orr, A. G.; Gong, S.; Gan, L.

doi:10.64898/2026.07.02.736124

bioRxiv · 10.64898/2026.07.02.736124

Humanized tauopathy chimeras uncover microglial and lncRNA strategies for neuroprotection

Qu, W.·Fan, L.·Jang, M. W.·Ye, P.·Cordes, E.·Aikedan, A.·Hu, W.·Nagiri, R. K.·Wong, M. Y.·Luo, W.·Blurton-Jones, M.·Tilgner, H. U.·Orr, A. G.·Gong, S.·Gan, L.

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Abstract

Human genetics implicates innate immunity as a key modifier of tau toxicity, yet human-specific neuroimmune mechanisms remain difficult to test in vivo. Here, we developed HuMiNAX, the first humanized iPSC-based neuroimmune xenograft model of tau-associated neurodegeneration, enabling human microglia to interact with human neurons and astrocytes in the adult mouse brain. In HuMiNAX, tau seeding induced aggregation only in mutation-carrying human neural grafts, causing neuron loss and inflammatory activation of human microglia. Progranulin-overexpressing human microglia dampened tau-associated inflammation, preserved neurons, and restored neuronal gene-expression and RNA-splicing programs, supporting microglial control of neuronal resilience. CRISPRi knockdown of the human-specific lncRNA HNRNPK-AS1 also protected neurons in HuMiNAX. These findings establish HuMiNAX as a human neuroimmune model of tauopathy and identify microglial and RNA-mediated strategies of neuronal resilience.

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Qu, W., Fan, L., Jang, M. W., Ye, P., Cordes, E., Aikedan, A., Hu, W., Nagiri, R. K., Wong, M. Y., Luo, W., Blurton-Jones, M., Tilgner, H. U., Orr, A. G., Gong, S., Gan, L.. 2026-07-03. Humanized tauopathy chimeras uncover microglial and lncRNA strategies for neuroprotection. https://doi.org/10.64898/2026.07.02.736124

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