The study investigates the propagation of Tau misfolding from the extracellular to the intracellular space in cells, a process hypothesized to contribute to the progression of Tauopathies. Tau, a microtubule-associated protein, aggregates in neurons and glia in various neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia. The authors hypothesize that extracellular Tau aggregates can transmit a misfolded state to intracellular Tau, similar to prions. They demonstrate that extracellular Tau aggregates, but not monomer, are taken up by cultured cells. These aggregates displace tubulin, co-localize with dextran (a marker of fluid-phase endocytosis), and induce fibrillization of intracellular full-length Tau. The induced intracellular fibrils are competent to seed fibril formation of recombinant Tau monomer in vitro. Additionally, the study shows that newly aggregated intracellular Tau transfers between co-cultured cells. These findings suggest that Tau aggregates can propagate a misfolded state from the outside to the inside of a cell, providing a potential mechanism for the spread of Tau pathology in the brain. This mechanism may have implications for understanding the progression of neurodegenerative diseases associated with protein misfolding.The study investigates the propagation of Tau misfolding from the extracellular to the intracellular space in cells, a process hypothesized to contribute to the progression of Tauopathies. Tau, a microtubule-associated protein, aggregates in neurons and glia in various neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia. The authors hypothesize that extracellular Tau aggregates can transmit a misfolded state to intracellular Tau, similar to prions. They demonstrate that extracellular Tau aggregates, but not monomer, are taken up by cultured cells. These aggregates displace tubulin, co-localize with dextran (a marker of fluid-phase endocytosis), and induce fibrillization of intracellular full-length Tau. The induced intracellular fibrils are competent to seed fibril formation of recombinant Tau monomer in vitro. Additionally, the study shows that newly aggregated intracellular Tau transfers between co-cultured cells. These findings suggest that Tau aggregates can propagate a misfolded state from the outside to the inside of a cell, providing a potential mechanism for the spread of Tau pathology in the brain. This mechanism may have implications for understanding the progression of neurodegenerative diseases associated with protein misfolding.