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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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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