Pneumonia‐induced cerebrovascular dysfunction: potential contributions to dementia

Abstract

AbstractBackgroundMany survivors of lung injury, including bacterial pneumonia and COVID‐19, suffer from incident dementia. Patients who have had pneumonia and other infections are at a higher risk for developing Alzheimer’s disease and related dementias (ADRD) (Chu et al., BBI, 2022, Sipila et al., Lancet Infec Dis, 2021, Girard et al., J Gen Intern Med, 2018). There is growing appreciation and strong evidence that neurovascular uncoupling, cerebral blood flow reductions and dysregulation, and breakdown of the blood‐brain barrier (BBB), including the loss of pericytes, are early events in the ADRD pathophysiological cascade. Furthermore, astrocytes and microglia are activated in the ADRD brain and can also disrupt cerebrovascular health and impact cognition. Because these are key events in ADRD, we aimed to determine the effects of bacterial pneumonia on the cerebrovascular system.MethodC57BL/6J mice were intratracheally infected with P. aeruginosa PA103 (ExoU and ExoT competent, 2.5×105 CFU) was introduced as a virulent bacterial strain for 24 or 48 hours. In addition, ΔPcrV (PA103ΔPcrV, 2.5×107 CFU), a mutant lacking a functional Type III secretion system was used for control. Following transcardial perfusion, brains were snap frozen in OCT and serially sectioned. Next, we performed immunofluorescence staining for CD13 (pericytes), lectin (endothelial cells), IgG (BBB leakage), Gfap (reactive astrocytes), and Iba1 (microglia).ResultSignificant BBB leakage of IgG was detected in both cortex and hippocampus 48 hours post‐infection with PA103 compared to ΔPcrV. Significant activation of astrocytes and microglia was detected 48 hours post‐PA103 infection compared to ΔPcrV. Pericyte coverage was unchanged in cortex and hippocampus both 24‐ and 48‐hours post‐infection with PA103 compared to ΔPcrV.ConclusionHere we have shown that bacterial pneumonia causes BBB breakdown and gliosis in young mice. Because BBB breakdown and gliosis are early events in many neurodegenerative diseases leading to cognitive dysfunction, understanding how pneumonia can accelerate these events is extremely timely and important. Future studies should focus on the mechanism(s) by which pneumonia causes cerebrovascular dysfunction and how this may increase ADRD.