The conversion of soluble tau protein to insoluble, hyperphosphorylated neurofibrillary tangles is a major hallmark leading to neuronal death observed in neurodegenerative tauopathies. Recent work suggests that extracellular, soluble tau binds to negatively charged heparan sulfate proteoglycans (HSPGs) available on the cell surface. In addition, LRP1 has recently been recognized as a major tau receptor, mediating tau uptake and spread. We hypothesized based on this data that monomeric tau would be endocytosed in both an HSPG- and LRP-dependent manner, activating intracellular signaling pathways that would regulate cellular phenotypes. Using live-cell confocal microscopy and flow cytometry, we show that soluble 0N4R monomers were rapidly endocytosed by SH-SY5Y and C6 glioma cells, via actin-dependent macropinocytosis. We also demonstrated the crucial role of HSPGs and LRP1 in cellular endocytosis of monomeric tau by observing reduced tau uptake in C6 glial cells with genetic knockouts of xylosyltransferase-1 – a key enzyme in HSPG synthesis – and LRP1. An ERK1/2 inhibition experiment showed that inhibiting the MEK-ERK1/2 signaling pathway attenuated IL-6 and IL-1β gene expression but not TNF-α . An LRP1 knockdown experiment led to an attenuated propensity for tau uptake and further elevated IL-6 gene expression. Collectively, our data suggest that tau has multiple extracellular binding partners that mediate its internalization through distinct mechanisms. Additionally, this study demonstrates the important role of both HSPG and LRP1 in regulating cellular immune responses to tau protein monomer, which provides a novel target for alleviating the neuroinflammatory environment before the formation of neurofibrillary tangles.