Fig. 8

Model of differential uptake and accumulation of Tau Monomers and aggregates in human neurons. Under physiological conditions, Tau Monomers exist in the extracellular environment and internalize neurons via LRP1-mediated endocytosis, which can be inhibited by LRP1 knockdown. Under pathological conditions, Tau aggregates in the extracellular environment internalize neurons mainly via HSPGs mediated endocytosis, which can be blocked by heparin or knockdown of HSPGs synthetizing enzymes such as EXT1 and EXT2. LRP1 may be partially involved in aggregate uptake in some types of neurons, which needs further investigation. The downregulation of VPS35, as a critical component of the retromer complex, reduced the accumulation of aggregates in both models of human neurons in this study. The endocytic vesicles inside the cells are depicted with faded colors since the internalization of Tau might be via endocytic vesicles and/or direct cytosol entry, which was not investigated in this study