Pulmonary Endothelial Tau Aggregation After Infection

Academic Article

Abstract

  • 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.
  • Published In

  • The FASEB Journal  Journal
  • Digital Object Identifier (doi)

    Author List

  • Lin MT; Choi CS; Gwin M; Voth S; Kolb C; Zhou C; Nelson AR; deWeever A; Koloteva A; Annamdevula NS
  • Volume

  • 36