Tau monomers and fibrils escape microglial clearance via distinct cellular mechanisms.

Tau monomers in human iPSC-derived microglia are internalized via LRP1 but are persistently recycled back extracellularly instead of reaching terminal lysosomes, unlike fibrils.

• Why it matters: Microglia clear toxic proteins yet may also promote tau spread, leaving unclear how distinct extracellular tau species are handled at the cellular level.
• What they did: Using high-resolution imaging and biochemical assays, the study tracked trafficking of extracellular tau monomers versus tau fibrils in human iPSC-derived microglia, testing LRP1, HSPG, TLR4, and interventions like heparin or anti-tau.
• The result: Tau fibrils primarily adhere via HSPG, activate TLR4, and drive pro-inflammatory cytokine release, with heparin or anti-tau dampening this response; APOE variants reduce microglia-tau interactions and tau uptake.

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