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1.
FASEB J ; 37(7): e23042, 2023 07.
Article in English | MEDLINE | ID: mdl-37358817

ABSTRACT

Patients who recover from hospital-acquired pneumonia exhibit a high incidence of end-organ dysfunction following hospital discharge, including cognitive deficits. We have previously demonstrated that pneumonia induces the production and release of cytotoxic oligomeric tau from pulmonary endothelial cells, and these tau oligomers can enter the circulation and may be a cause of long-term morbidities. Endothelial-derived oligomeric tau is hyperphosphorylated during infection. The purpose of these studies was to determine whether Ser-214 phosphorylation of tau is a necessary stimulus for generation of cytotoxic tau variants. The results of these studies demonstrate that Ser-214 phosphorylation is critical for the cytotoxic properties of infection-induced oligomeric tau. In the lung, Ser-214 phosphorylated tau contributes to disruption of the alveolar-capillary barrier, resulting in increased permeability. However, in the brain, both the Ser-214 phosphorylated tau and the mutant Ser-214-Ala tau, which cannot be phosphorylated, disrupted hippocampal long-term potentiation suggesting that inhibition of long-term potentiation was relatively insensitive to the phosphorylation status of Ser-214. Nonetheless, phosphorylation of tau is essential to its cytotoxicity since global dephosphorylation of the infection-induced cytotoxic tau variants rescued long-term potentiation. Collectively, these data demonstrate that multiple forms of oligomeric tau are generated during infectious pneumonia, with different forms of oligomeric tau being responsible for dysfunction of distinct end-organs during pneumonia.


Subject(s)
Antineoplastic Agents , Pneumonia , Humans , Phosphorylation , tau Proteins/genetics , tau Proteins/metabolism , Endothelial Cells/metabolism , Lung/metabolism
2.
J Biol Chem ; 298(1): 101482, 2022 01.
Article in English | MEDLINE | ID: mdl-34896150

ABSTRACT

Patients who recover from nosocomial pneumonia oftentimes exhibit long-lasting cognitive impairment comparable with what is observed in Alzheimer's disease patients. We previously hypothesized that the lung endothelium contributes to infection-related neurocognitive dysfunction, because bacteria-exposed endothelial cells release a form(s) of cytotoxic tau that is sufficient to impair long-term potentiation in the hippocampus. However, the full-length lung and endothelial tau isoform(s) have yet to be resolved and it remains unclear whether the infection-induced endothelial cytotoxic tau triggers neuronal tau aggregation. 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, the cells were infected with Pseudomonas 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 in tau knockout cells. After bacterial lung infection, brain homogenates from WT mice, but not from tau knockout mice, initiated tau aggregation. Thus, we conclude that bacterial pneumonia initiates the release of lung endothelial-derived cytotoxic tau, which is capable of propagating a neuronal tauopathy.


Subject(s)
Lung Diseases , Pneumonia, Bacterial , Tauopathies , tau Proteins , Animals , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/microbiology , Cognitive Dysfunction/pathology , Endothelial Cells/metabolism , Endothelial Cells/microbiology , Endothelial Cells/pathology , Humans , Lung/blood supply , Lung Diseases/metabolism , Lung Diseases/microbiology , Lung Diseases/pathology , Mice , Pneumonia, Bacterial/metabolism , Pneumonia, Bacterial/microbiology , Pneumonia, Bacterial/pathology , Protein Isoforms , Pseudomonas aeruginosa , Tauopathies/genetics , Tauopathies/metabolism , Tauopathies/pathology , tau Proteins/chemistry , tau Proteins/genetics , tau Proteins/metabolism
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