Lung endothelial cytopathic tau is sufficient to impair long-term potentiation during infection

Cytopathic tau variants are recovered from the lung, circulation, and brain following lower respiratory tract infection. Cytopathic tau injures the lung and brain, yet its cellular origin during infection is unknown. Here, we assessed whether lung capillary endothelium is a source of cytopathic tau that contributes to brain injury during infection. Alveolar-capillary permeability was higher in tau knockout than wild type mice following sublethal Pseudomonas aeruginosa infection, indicating endogenously expressed tau contributes to integrity of the lung’s gas exchange unit. Hippocampal long-term potentiation was inhibited following sublethal infection in wild type but not tau knockout mice, even though the blood-brain barrier was not overtly disrupted. Tau expression solely in lung capillaries of tau knockout mice was sufficient to restore alveolar-capillary barrier integrity and impair hippocampal long-term potentiation following sublethal infection. Thus, endogenous lung capillary endothelial tau preserves alveolar-capillary integrity, yet it is a source of cytopathic tau that injures the brain during pneumonia.