Pseudomonas aeruginosa Exoenzymes U and Y Induce a Transmissible Endothelial Tauopathy

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Here, we tested the hypothesis that Pseudomonas aeruginosa type 3 secretion system effectors ExoY and ExoU induce endothelial tau oligomerization and release, causing transmissible cytotoxicity characteristic of an infectious tauopathy. Both the bacterial delivery of ExoY and ExoU, and the conditional expression of an activity‐attenuated ExoU, induced time‐dependent pulmonary microvascular endothelial cell (PMVEC) gap formation that was paralleled by loss of intracellular tau and concomitant appearance of extracellular tau oligomers. Transfer of tau oligomers in filtered supernatant onto naïve endothelial cells resulted in the intracellular accumulation of oligomeric tau inclusions accompanied by cytotoxicity, as determined by inter‐endothelial gap formation and decreased endothelial network stability in Matrigel. Tau oligomer monoclonal antibodies captured monomeric tau from filtered supernatant, but did not retrieve higher molecular mass tau oligomers, and did not rescue the cytotoxic effects of tau. Since cytotoxic effects were not rescued, we combined an electrophoresis and electroelution approach to recover the high molecular mass tau oligomers, treat PMVECs with these oligomers, and recapitulate cytotoxicity. Thus, we provide the first evidence for a pathophysiological stimulus that induces endothelial tau oligomerization, release and transmissible cytotoxicity, characteristic of an endothelial tauopathy.