Tau pathology in neurodegenerative diseases like Alzheimer's and frontotemporal dementia involves the misfolding and aggregation of the microtubule-associated protein Tau. While Tau is typically intracellular, it is found in extracellular aggregates and can be detected in cerebrospinal fluid. These aggregates can enter cells and induce misfolding of intracellular Tau, similar to prion propagation. The study shows that extracellular Tau aggregates are internalized by cultured cells, displace tubulin, co-localize with dextran, and induce fibrillization of intracellular full-length Tau. These fibrils can seed the aggregation of recombinant Tau monomer. Additionally, newly formed intracellular Tau aggregates can transfer between co-cultured cells. These findings suggest that Tau aggregates can propagate a misfolded state from the outside to the inside of a cell, which may explain how protein misfolding spreads in tauopathies. This mechanism could have implications for understanding the progression of other neurodegenerative diseases associated with protein misfolding. The study used various techniques, including atomic force microscopy, flow cytometry, and immunofluorescence, to demonstrate the internalization and propagation of Tau aggregates. The results indicate that extracellular Tau aggregates enter cells via endocytosis and induce intracellular aggregation, which can then transfer between cells. This process may involve direct interaction between exogenous and endogenous Tau proteins, leading to the spread of misfolded Tau throughout the brain. The study also highlights the potential role of Tau in trans-cellular propagation, suggesting that Tau itself may be the agent responsible for spreading misfolding. The findings contribute to the understanding of how protein misfolding spreads in neurodegenerative diseases and provide a mechanism for the propagation of Tau pathology.Tau pathology in neurodegenerative diseases like Alzheimer's and frontotemporal dementia involves the misfolding and aggregation of the microtubule-associated protein Tau. While Tau is typically intracellular, it is found in extracellular aggregates and can be detected in cerebrospinal fluid. These aggregates can enter cells and induce misfolding of intracellular Tau, similar to prion propagation. The study shows that extracellular Tau aggregates are internalized by cultured cells, displace tubulin, co-localize with dextran, and induce fibrillization of intracellular full-length Tau. These fibrils can seed the aggregation of recombinant Tau monomer. Additionally, newly formed intracellular Tau aggregates can transfer between co-cultured cells. These findings suggest that Tau aggregates can propagate a misfolded state from the outside to the inside of a cell, which may explain how protein misfolding spreads in tauopathies. This mechanism could have implications for understanding the progression of other neurodegenerative diseases associated with protein misfolding. The study used various techniques, including atomic force microscopy, flow cytometry, and immunofluorescence, to demonstrate the internalization and propagation of Tau aggregates. The results indicate that extracellular Tau aggregates enter cells via endocytosis and induce intracellular aggregation, which can then transfer between cells. This process may involve direct interaction between exogenous and endogenous Tau proteins, leading to the spread of misfolded Tau throughout the brain. The study also highlights the potential role of Tau in trans-cellular propagation, suggesting that Tau itself may be the agent responsible for spreading misfolding. The findings contribute to the understanding of how protein misfolding spreads in neurodegenerative diseases and provide a mechanism for the propagation of Tau pathology.