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Pseudomonas aeruginosa pneumonia elicits endothelial cell release of cytotoxic amyloids that can be recovered from the bronchoalveolar lavage and cerebrospinal fluids of critically ill patients. Introduction of these cytotoxic amyloids into the lateral ventricle impairs learning and memory in mice. However, it is unclear whether the amyloids of lung origin (1) are neurotropic, and (2) cause structural remodeling of hippocampal dendrites. Thus, we used electrophysiological studies in brain slices and structural analysis of post-mortem tissues obtained from animals exposed to endothelium-derived amyloids to assess these issues. The amyloids were administered via three different routes, by intracerebroventricular, intratracheal, and intraperitoneal injections. Synaptic long-term potentiation was abolished following intracerebroventricular amyloid injection. Fluorescence dialysis or Golgi-impregnation labeling showed reduced dendritic spine density and destabilized spines of hippocampal pyramidal neurons 4 weeks after intracerebroventricular amyloid injection. In comparison, endothelial amyloids introduced to the airway caused the most prominent dendritic spine density reduction, yet intraperitoneal injection of these amyloids did not affect spine density. Our findings indicate that infection-elicited lung endothelial amyloids are neurotropic and reduce neuronal dendritic spine density in vivo. Amyloids applied into the trachea may either be disseminated through the circulation and cross the blood-brain barrier to access the brain, initiate feed-forward amyloid transmissibility among cells of the blood-brain barrier or access the brain in other ways. Nevertheless, lung-derived amyloids suppress hippocampal signaling and cause injury to neuronal structure.

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Patients who recover from nosocomial pneumonia oftentimes exhibit long‐lasting cognitive impairment comparable to what is observed in Alzheimer’s Disease patients. We previously hypothesized that the lung endothelium contributes to infection‐related neurocognitive dysfunction, since bacteria‐exposed endothelial cells release a form(s) of cytotoxic tau that is sufficient to impair long‐term potentiation in the hippocampus. However, lung endothelial tau isoform(s) have yet to be resolved and it remains unclear whether the infection‐induced endothelial cytotoxic tau can trigger neuronal tau aggregation which is the major hallmark of several neuropathologies. Here, we demonstrate that lung endothelial cells express a big tau isoform and three additional tau isoforms that are similar to neuronal tau, each containing four microtubule‐binding repeat domains, and that tau is expressed in lung capillaries in vivo. To test whether infection elicits endothelial tau capable of causing transmissible tau aggregation, cells were infected with P. aeruginosa. The infection‐induced tau released from endothelium into the medium induced neuronal tau aggregation in reporter cells, including reporter cells that express either the four microtubule‐binding repeat domains or the full‐length tau. Infection‐induced release of pathological tau variant(s) from endothelium, and the ability of the endothelial‐derived tau to cause neuronal tau aggregation, was abolished using tau knockout cells. After bacterial lung infection, brain homogenates from wild‐type mice, but not from tau knockout mice, initiated tau aggregation. Notably, plasma samples obtained from pneumonia‐positive patients showed significantly higher tau aggregation activity when compared to pneumonia‐negative plasma samples. Thus, bacterial pneumonia initiates the release of lung endothelial‐derived cytotoxic tau into the circulation, which is capable of propagating a neuronal tauopathy.

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