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Principal Investigator: Amy R Nelson
Organization: UNIVERSITY OF SOUTH ALABAMA
Fiscal Year: 2024
Award: $684,526
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <2-photon><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><APOE e4><APOE-ε4><APOEε4><Address><Adeno-Associated Viruses><Adventitial Cell><Alzheimer beta-Protein><Alzheimer's Amyloid beta-Protein><Alzheimer's amyloid><Amentia><Amyloid><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid Substance><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Antibodies><Apolipoproteins><Assay><Autopsy><Aβ><Bacterial Pneumonia><Bioassay><Biological Assay><Biological Markers><Biology><Blood><Blood - brain barrier anatomy><Blood Circulation><Blood Plasma><Blood Reticuloendothelial System><Blood-Brain Barrier><Bloodstream><Brain><Brain Nervous System><Brain hemodynamics><COVID-19 virus><COVID19 virus><Cerebrovascular Circulation><Cerebrovascular system><Clinical><Clinical Research><Clinical Study><CoV-2><CoV2><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Data><Dementia><Dendritic Spines><Dependoparvovirus><Dependovirus><Disturbance in cognition><Dysfunction><Encephalon><Endothelial Cells><Endothelium><Event><Experimental Models><Financial Hardship><Functional disorder><Gardol><Genetic predisposing factor><Genotype><Gliosis><Healthcare><Hemato-Encephalic Barrier><Hospital Mortality><Impaired cognition><Impairment><In Vitro><In-house Mortalities><Incidence><Infection><Inhospital Mortality><Injury><Intensive Care Units><Isoforms><Knowledge><Learning><Length of Stay><Link><Lung><Lung Respiratory System><MT-bound tau><Maintenance><Memory><Methodology><Mice><Mice Mammals><Murine><Mus><N-lauroyl sarcosine><N-lauroylsarcosinate><N-lauroylsarcosine><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurologic Deficit><Neurons><Nosocomial pneumonia><Number of Days in Hospital><Operative Procedures><Operative Surgical Procedures><Organ><P aeruginosa><P. aeruginosa><P. aeruginosa infection><PDGF Receptors><Pathologic><Pathology><Patients><Pericapillary Cell><Pericytes><Peripheral><Perivascular Cell><Phosphorylation><Physiopathology><Plasma><Plasma Serum><Platelet-Derived Growth Factor Receptor><Pneumonia><Post-Operative><Postoperative><Postoperative Period><Production><Protein Isoforms><Protein Phosphorylation><Pseudomonas aeruginosa><Pseudomonas aeruginosa infection><Pseudomonas pyocyanea><QOL><Quality of life><Regulation><Resolution><Reticuloendothelial System, Serum, Plasma><Rouget Cells><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Sepsis><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Severities><Speed><Surgical><Surgical Interventions><Surgical Procedure><Survivors><Syndrome><Tauopathies><Testing><Variant><Variation><Viral Pneumonia><Work><Wuhan coronavirus><a beta peptide><abeta><abnormal brain function><abnormally aggregated tau protein><adeno associated virus group><amyloid beta><amyloid-b protein><apo E-4><apo E4><apo epsilon4><apoE epsilon 4><apoE-4><apoE4><apolipoprotein E epsilon 4><apolipoprotein E-4><apolipoprotein E4><bacteria pneumonia><beta amyloid fibril><bio-markers><biologic marker><biomarker><blood flow in brain><blood infection><blood vessels in the brain><bloodbrain barrier><bloodstream infection><brain blood circulation><brain blood dynamics><brain blood flow><brain blood vessels><brain dysfunction><brain impairment><brain vasculature><cerebral blood flow><cerebral blood vessel><cerebral circulation><cerebral hemodynamics><cerebral vasculature><cerebrocirculation><cerebrovascular blood flow><cerebrovascular vessels><cerebrovasculature><cognitive defects><cognitive dysfunction><cognitive loss><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytokine><cytotoxic><dendrite spine><density><disparity in health><dysfunctional brain><experience><experiment><experimental research><experimental study><experiments><filamentous tau inclusion><financial adversity><financial burden><financial distress><financial insecurity><financial strain><financial stress><genetic risk factor><hCoV19><health care><health disparity><healthcare-associated pneumonia><hemodynamics><hospital acquired pneumonia><hospital associated pneumonia><hospital days><hospital length of stay><hospital stay><human tissue><imaging study><infected with P. aeruginosa><infected with Pseudomonas aeruginosa><inherited factor><injuries><innovate><innovation><innovative><intra-vital microscopy><intravital microscopy><microorganism><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-bound tau><mild cognitive disorder><mild cognitive impairment><nCoV2><natural aging><necropsy><neuro-vascular><neuro-vascular damage><neuro-vascular injury><neuro-vascular unit><neuronal><neuropathologic tau><neuropathological tau><neurovascular><neurovascular damage><neurovascular injury><neurovascular unit><normal aging><normative aging><novel><paired helical filament of tau><pathogen><pathophysiology><postmortem><pre-clinical><preclinical><prevent><preventing><pulmonary><resolutions><response><sarcosyl NL><sarkosyl><sarkosyl L><sarkosyl NL><sarkosyl NL 30><self-aggregate tau><sodium N-laurylsarcosinate><soluble amyloid precursor protein><surgery><tau><tau PHF><tau Proteins><tau accumulation><tau aggregate><tau aggregation><tau associated neurodegeneration><tau associated neurodegenerative process><tau factor><tau fibrillization><tau filament><tau induced neurodegeneration><tau mediated neurodegeneration><tau neurodegenerative disease><tau neurofibrillary tangle><tau neuropathology><tau oligomer><tau paired helical filament><tau polymerization><tau-tau interaction><tauopathic neurodegenerative disorder><tauopathy><two-photon><τ Proteins><τ aggregation>