Tau monomers and fibrils escape microglial clearance via distinct cellular mechanisms

Tauopathies, such as Alzheimer’s disease, are neurodegenerative disorders characterized by the accumulation and propagation of toxic extracellular forms of the microtubule-associated protein tau across brain regions. Microglia, the resident macrophages of the brain, are known for clearing and degrading toxic proteins. However, emerging evidence suggests that microglia also enhance tau spreading. To dissect the molecular mechanisms underlying microglial responses to extracellular tau, we use high-resolution imaging and biochemical approaches to assess the trafficking dynamics of different extracellular tau species in human induced pluripotent stem cell-derived microglia. Here we find that tau monomers are internalized by microglia via cell-surface LRP1 receptors but fail to reach terminally degradative lysosomes; instead, they are persistently recycled back to the extracellular space. In contrast, tau fibrils are not internalized and primarily adhere to the cell surface through an HSPG-dependent mechanism, triggering TLR4-mediated microglial activation and the release of pro-inflammatory cytokines. Heparin or anti-tau treatments dampen tau fibril-mediated microglial activation. In addition, disease-associated variants of the Alzheimer’s disease-related protein APOE reduce microglia–tau interactions, further reducing tau uptake. Together, these findings demonstrate that microglia fail to efficiently clear extracellular tau monomers and fibrils through mechanistically distinct cellular processes, emphasizing the need for tailored therapeutic strategies to enhance extracellular tau clearance in neurodegenerative diseases. Kulkarni et al. show distinct fates of monomeric versus fibrillar tau in human induced pluripotent stem cell-derived microglia. Monomeric tau is internalized but does not reach degradative lysosomes; fibrillar tau adheres to the cell surface and triggers microglial activation.