Extracellular monomeric and aggregated tau efficiently enter human neurons through overlapping but distinct pathways

Abstract A current working model is that Alzheimer's disease actively spreads from diseased to healthy neurons, mediated by transfer of extracellular, abnormal, disease-specific forms of the microtubule-associated protein tau. It is currently unclear whether transfer of tau between neurons is a toxic gain-of-function process in dementia, or reflects a constitutive biological process. We report two mechanisms of entry of monomeric tau to neurons: a rapid early dynamin-dependent phase, and a second, slower actin-dependent phase, suggesting that monomeric tau enters neurons via rapid saturable clathrin-mediated endocytosis and also by bulk endocytosis. Aggregated tau entry is independent of actin polymerisation and largely dynamin dependent, consistent with clathrin-mediated endocytosis and distinct from macropinocytosis, the major route for aggregated tau entry reported for non-neuronal cells. Anti-tau antibodies abrogate tau entry into neurons, with tau carrying antibody with it into neurons, indicating that antibody binding is insufficient to prevent neuronal tau entry.