Amyloid-mediated cognitive dysfunction in bacterial pneumonia after TBI

About This Grant

Project Summary/Abstract Bacterial pneumonia leads to harmful clinical manifestations that persist long after resolution of the primary infection, including cognitive decline; also, patients hospitalized for community-acquired or nosocomial pneumonia develop cognitive impairment—including the risk of developing Alzheimer’s disease (AD)-related dementia. Pseudomonas (P.) aeruginosa is a Gram-negative bacterium and common cause of nosocomial pneumonia in intensive care units (ICU) and traumatic brain injury (TBI) is a risk factor for secondary bacterial pneumonia, in addition to being a risk factor for cognitive decline. Our preliminary clinical data demonstrate that TBI patients have increased rates of bacterial pneumonia. In our murine model, mice with P. aeruginosa pneumonia after TBI have significant learning and memory deficits compared to mice with TBI alone. Preliminary data indicate that alveolar epithelial cells release amyloid beta (Aβ) after P. aeruginosa infection, Aβ accumulates in the bronchoalveolar lavage fluid of critically ill patients, and Aβ stimulates expression of tumor necrosis factor alpha (TNF-α) in alveolar macrophages, suggesting a novel link from pulmonary Aβ to inflammatory responses. We have published that P. aeruginosa elicits oligomeric Aβ from pulmonary cells, infection-induced Aβ impairs cognitive function, and that Aβ accumulates in the BALF of pneumonia patients that correlates with end-organ dysfunction. Finally, Aβ and TNFα activate Neuronal Wiskott–Aldrich syndrome protein (NWASP) in brain microvascular endothelial cells, resulting in BBB dysfunction and increased permeability. Data from us and others suggest a novel link between Aβ released from pulmonary epithelial cells and cognitive dysfunction in mice with bacterial pneumonia after TBI, and Aβ-enhanced inflammatory responses as the potential mechanism. Therefore, we hypothesize that bacterial pneumonia after TBI induces Aβ expression and dissemination from alveolar epithelial cells and that Aβ amplifies lung and brain inflammation in an NWASP-dependent manner that worsens lung barrier and cognitive dysfunction. Our strategies aim to test that P. aeruginosa-induced Aβ dissemination enhances NWASP-mediated inflammation, leading to exacerbated cognitive dysfunction in a murine model of bacterial pneumonia after TBI. Aim 1 will determine the molecular mechanism by which bacterial pneumonia after TBI worsens lung barrier and cognitive dysfunction. Aim 2 will define the mechanism(s) of BBB breakdown mediated by NWASP and its role in cognitive dysfunction in a murine model of bacterial pneumonia after TBI. Aim 3 will examine the role of infection-induced amyloids on cognitive dysfunction in mice and determine the level of amyloids in clinically-relevant, archived, de-identified human patient samples. There is little data regarding the impact of bacterial pneumonia on cognitive dysfunction after TBI and this is a significant clinical gap that has yet to be examined; understanding how bacterial pneumonia after TBI impacts cognitive dysfunction would lead to advances in sepsis research and critical care medicine.