Microglia internalize tau monomers and fibrils using distinct receptors but similar mechanisms

Abstract INTRODUCTION Alzheimer's disease (AD) and other tauopathies are characterized by intracellular aggregates of microtubule‐associated protein tau that are actively released and promote proteopathic spread. Microglia engulf pathological proteins, but how they endocytose tau is unknown. METHODS We measured endocytosis of different tau species by microglia after pharmacological modulation of macropinocytosis or clathrin‐mediated endocytosis (CME) or antagonism/genetic depletion of known tau receptors heparan‐sulfate proteoglycans (HSPGs) and low‐density lipoprotein receptor‐related protein 1 (LRP1). RESULTS Dynamin inhibition decreased microglial endocytosis of all tested tau species. Meanwhile, HSPG antagonism blocked only fibril uptake, and LRP1 antagonism or genetic depletion inconsistently inhibited the endocytosis of fibrils and monomers. Cre recombinase robustly enhanced tau uptake with partial selectivity for fibrils. DISCUSSION These data show that microglia take up both tau monomers and aggregates via a dynamin‐dependent form of endocytosis (eg, CME) but may differ in using HSPGs for entry depending on species. Highlights Microglial endocytosis of tau monomers and fibrils is dynamin‐dependent. HSPG antagonism blocks microglial uptake of tau fibrils but not monomers. LRP1 antagonism or knockdown inconsistently inhibits tau uptake. TAT‐Cre stimulates semi‐selective uptake of fibrils over monomers.