Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Postoperative pneumonia occurs in ~2-8% of patients following various surgeries and increases the length of hospital stay and mortality. Pneumonia is a common cause of sepsis. Some pneumonia survivors, including those with post-intensive care unit syndrome, suffer from cognitive deficits, reducing their quality of life and inflicting healthcare and financial hardships. Strikingly, pneumonia-associated microorganisms (e.g., P. aeruginosa) trigger lung endothelial production and release of several cytotoxic amyloids (e.g., tau and Aβ) that are key pathological hallmarks of dementia. Cytotoxic tau produced by lung endothelial cells in response to bacterial pneumonia infection accumulates in the brain, reduces dendritic spine density, impairs learning and memory, and causes neuronal tauopathy. We recently found that P. aeruginosa infection causes blood-brain barrier breakdown and gliosis. There is growing appreciation and strong evidence that neurovascular uncoupling, cerebral blood flow reductions and dysregulation, and breakdown of the blood-brain barrier, including the loss of pericytes, are early events leading to cognitive decline and dementia, including in the setting of pneumonia and infections. Apolipoprotein (APOE)-ε4 is the greatest genetic risk factor for sporadic dementia, increases infection severity (e.g., SARS-CoV-2) and promotes blood-brain barrier damage and pericyte degeneration. Whether pneumonia-elicited lung endothelial cytotoxic tau variants initiate blood-brain barrier breakdown to induce neurovascular unit dysfunction (e.g., pericyte injury, gliosis, and impaired hemodynamics), and whether APOE- ε4-induced neurovascular unit dysfunction exacerbates the negative impact of lung endothelial tau on the brain remains to be determined and are the focus of this study. Using state-of-the-art methodologies, this proposal innovatively uses 1) fast-speed, high-resolution two-photon intravital microscopy, 2) quantitative tau and neurovascular unit plasma assays, 3) pathological assessment of lung tau and neurovascular unit dysfunction in post-mortem human tissue, 4) lung endothelium targeted mice and adeno-associated viruses, and 5) anti-tau antibodies. This proposal tests the scientifically supported and novel hypotheses that 1) lung endothelial tau disrupts the neurovascular unit, 2) APOE-ε4 exacerbates the impact of lung endothelial tau on the neurovascular unit, and 3) anti-tau antibodies to prevent neurovascular unit dysfunction caused by pneumonia. This is a translational preclinical project bridging in vitro experiments, experimental models and clinical samples, and is pioneering in that it synthesizes experts in lung and brain biology to understand the impact of pneumonia-elicited lung endothelial tau on neurovascular unit functions, with consideration of health disparities.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
