Tau internalization: A complex step in tau propagation

•The possible internalization pathways of Tau are many and varied.•The internalization pathway of Tau is determined by its conformation, modification, and donor/recipient cell type.•HSPGs in the extracellular matrix play a very important role in different internalization pathways of Tau. Aggregation of microtubule-associated protein Tau (MAPT) may underlie abnormalities of the intracellular matrix and neuronal death in tauopathies. Tau proteins can be secreted to the extracellular space and internalized into adjacent cells. The internalization of Tau is a complex but critical step in Tau propagation. This review summarizes the internalization pathways of Tau, including macropinocytosis, Clathrin-mediated endocytosis (CME), lipid raft dependent endocytosis, Tunneling nanotubes dependent endocytosis (TNTs) and phagocytosis. The conformation of Tau fibrils and the types of recipient cell determine the internalization pathway. However, the HSPGs-dependent endocytosis seems to be the predominant pathway of Tau internalization. After internalization, Tau fibrils undergo clearance and seeding. Imbalance among Tau secretion, internalization and clearance may result in the propagation of misfolded Tau in the brain, thereby inducing Tauopathies. A better understanding of the internalization of Tau proteins may facilitate the discovery of novel therapeutic strategies to block the propagation of Tau pathology.