Tau endo-lysosomal processing in human iPSC-derived microglia is impacted by tau aggregation state, but not by microglial activation status

Shultz, A.; Vincze, A.; Yau, T. T.; Poirier, E. L.; Rauch, J. N.

doi:10.1101/2025.06.23.661190

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bioRxiv · 10.1101/2025.06.23.661190

Tau endo-lysosomal processing in human iPSC-derived microglia is impacted by tau aggregation state, but not by microglial activation status

Shultz, A.·Vincze, A.·Yau, T. T.·Poirier, E. L.·Rauch, J. N.

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Abstract

Microglia are the tissue resident macrophages of the brain and their contribution to tau pathology progression remains to be fully understood. In this study, we developed a quantitative platform to elucidate the processing of extracellular tau within human induced pluripotent stem cell (iPSC)-derived microglia. We show that iPSC-derived microglia internalize monomeric and fibrillar tau through different cellular mechanisms and with different clearance kinetics. Acute inflammatory activation of microglia alters tau endocytosis, but surprisingly does not impact tau clearance. These results highlight the importance of the microglial endo-lysosome system as a regulator of tau pathology that is decoupled from acute microglial activation. HighlightsO_LIHuman iPSC-derived microglia endocytose tau using divergent cellular mechanisms C_LIO_LINanoBiT system can measure tau endocytosis and degradation in cells C_LIO_LIAggregation of tau impacts the rate of extracellular clearance after endocytosis C_LIO_LIAcute inflammation affects total endocytosed tau, but not clearance in microglia C_LI

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Shultz, A., Vincze, A., Yau, T. T., Poirier, E. L., Rauch, J. N.. 2025-06-25. Tau endo-lysosomal processing in human iPSC-derived microglia is impacted by tau aggregation state, but not by microglial activation status. https://doi.org/10.1101/2025.06.23.661190

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