Our work is consistent with that of others demonstrating that neuronal uptake of tau seeds occurs in a clathrin-independent, but dynamin1-and actin-dependent mechanism. Herein, we demonstrate for the first time the critical involvement of Rac1 in this process. The use of pharmacological and genetic approaches in neuronal uptake and seeding assays shows the relevance of this pathway in tau spreading pathology further strengthening findings by other groups. While we previously suggested CME in the neuronal uptake of Tau because of the demonstrated role of Bin1 (14), our current **data** prove that unequivocally clathrin does not play a role. Selectively inhibiting downstream effectors of Rac1 involved in actin polymerization and endocytosis, including Arp2/3, N-WASP, and PAK1, did not reduce tau seeds internalization. As mentioned before, clathrin-independent, dynamin-dependent endocytosis as well as macropinocytosis has been proposed previously as a mechanism by which tau aggregates are internalized by cell lines (16,17) or human neurons (18). The **data** presented here show that also in neurons, several proteins that are part of the core machineries involved in clathrin-independent endocytosis or macropinocytosis, such as dynamin1, actin, and Rac1, are involved in the uptake of Tau seeds. However, molecular players functioning in macropinocytosis, like PAK1, could not be linked to tau seeds uptake (58,59). Therefore, we conclude that the uptake of tau seeds by neurons is carried out by a distinct endocytosis mechanism that is dependent on dynamin and Rac1 and independent of clathrin.