Infection‐induced endothelial amyloids impair memory

Abstract

Patients with nosocomial pneumonia exhibit elevated levels of neurotoxic amyloid and tau proteins in the cerebrospinal fluid (CSF). In vitro studies indicate that pulmonary endothelium infected with clinical isolates of either Pseudomonas aeruginosa, Klebsiella pneumoniae, or Staphylococcus aureus produces and releases cytotoxic amyloid and tau proteins. However, the effects of the pulmonary endothelium‐derived amyloid and tau proteins on brain function have not been elucidated. Here, we show that P. aeruginosa infection elicits accumulation of detergent insoluble tau protein in the mouse brain and inhibits synaptic plasticity. Mice receiving endothelium‐derived amyloid and tau proteins via intracerebroventricular injection exhibit a learning and memory deficit in object recognition, fear conditioning, and Morris water maze studies. We compared endothelial supernatants obtained after the endothelia were infected with P. aeruginosa possessing an intact [P. aeruginosa isolated from patient 103 (PA103) supernatant] or defective [mutant strain of P. aeruginosa lacking a functional type 3 secretion system needle tip complex (ΔPcrV) supernatant] type 3 secretion system. Whereas the PA103 supernatant impaired working memory, the ΔPcrV supernatant had no effect. Immunodepleting amyloid or tau proteins from the PA103 supernatant with the A11 or T22 antibodies, respectively, overtly rescued working memory. Recordings from hippocampal slices treated with endothelial supernatants or CSF from patients with or without nosocomial pneumonia indicated that endothelium‐derived neurotoxins disrupted the postsynaptic synaptic response. Taken together, these results establish a plausible mechanism for the neurologic sequelae consequent to nosocomial bacterial pneumonia.—Balczon, R., Pittet, J.‐F., Wagener, B. M., Moser, S. A., Voth, S., Vorhees, C. V., Williams, M. T., Bridges, J. P., Alvarez, D. F., Koloteva, A., Xu, Y., Zha, X.‐M., Audia, J. P., Stevens, T., Lin, M. T. Infection‐induced endothelial amyloids impair memory. FASEB J. 33, 10300–10314 (2019). http://www.fasebj.org

Cystatin C regulates the cytotoxicity of infection‐induced endothelial‐derived β‐amyloid

“…Supernatant generated following inoculation of PMVECs with DPcrV, a strain that lacks a functional type III secretion system, does not contain secreted cytotoxic Ab and oligomeric tau whereas supernatant produced using strain PA103 does contain the cytotoxic forms ( Fig. 1) [19][20][21].…”

“…Previously, we had demonstrated that treatment with a 10‐fold excess of HFIP to PA103 supernatant resulted in loss amyloid epitopes [19]. To assess the effects of HFIP on the structure of endothelial‐derived toxic amyloids at lower ratios of HFIP to supernatant, immunoblot analysis was performed using A11 anti‐amyloid antibody, which we have shown previously recognizes both endothelial‐derived Aβ and oligomeric tau [20,21]. As shown in Fig.…”

“…According to this scheme, the long-lived, self-replicating Ab and tau would be capable of being transported throughout the body where they could subsequently re-infect the surviving patient's cells leading to organ failure sometime following hospital discharge. Support for this possibility was shown in studies in which cell culture supernatants generated following infection of cultured endothelial cells, as well as cerebrospinal fluid from pneumonia patients, were able to disrupt long-term potentiation in rat brain slices [20] and memory in treated animals [21]. Experiments in progress are further investigating the possibility that infection-induced lung-derived Ab and oligomeric tau are transported throughout the circulation leading to poor patient outcomes.…”

Exoenzyme Y Contributes to End-Organ Dysfunction Caused by Pseudomonas aeruginosa Pneumonia in Critically Ill Patients: An Exploratory Study

“…Like tau, these amyloids demonstrated the ability to propagate in naïve endothelial cells and also displayed some insensitivity to degradation, indicating the behavior of a prion-like entity. In addition to being detected in the bronchoalveolar lavage fluid of patients with P. aeruginosa, they also disrupt long-term potentiation in the rat hippocampus [22,23]. Thus, generation of transmissible and cytotoxic amyloids within the lung may contribute to end-organ dysfunction that is due to ExoY and ExoU.…”

“…Finally, recent studies indicate that ExoY is involved in the breakdown of peripheral microtubules and subsequent release of tau and amyloid β. These events lead to decreased endothelial cell barrier integrity and increased end-organ injury in both the pulmonary system and the brain [21][22][23].…”