Tracking tau and cellular responses in human iPSC-microglia from uptake to seedable secretion in extracellular vesicles

The templated spread of tau aggregates in tauopathies has been attributed to neuron-to-neuron spread, but microglia have also been implicated, in mouse studies. Here we examine in detail the uptake, processing, release and seeding of tau using human iPS-derived microglia (iMGL). We show that tau is taken up by iMGL via LRP1 and heparan sulfate proteoglycans, with a role for LRRK2 in LRP1 trafficking, and that phagocytosed fibrils can escape into the cytoplasm. Tau monomer has minimal effect on iMGL, but recombinant or brain-derived tau fibrils induce a shift towards chemokine and interferon response subtypes, alongside downregulation of homeostatic and MHC genes. Endogenous tau protein is undetectable in iMGL, and monomeric tau is digested to completion, but fibrillar tau is degraded inefficiently and becomes phosphorylated on two specific residues. Finally, undegraded tau is released, including secretion as fibrils visualised by cryo-EM within extracellular vesicles, and can seed downstream neurons