Pneumonia-induced microglial activation causes blood-brain barrier breakdown, astrocyte activation, and tau pathology

PROJECT SUMMARY / ABSTRACT Many survivors of respiratory infections (i.e., pneumonia, and SARS-CoV-2) have subsequent incident dementia causing decreased quality of life and are at a higher risk of developing Alzheimer’s disease and related dementias. The cause of this association between pneumonia and dementia is unknown. It is also unknown how

bacterial pneumonia causes neurovascular unit dysfunction. Pseudomonas aeruginosa is a pathogen capable of causing bacterial pneumonia and can elicit cytotoxic tau from the mouse lung and induce neuronal tau seeding, reduce dendritic spine density, and impair synaptic plasticity and cognition in mice. Additionally, I have shown

that P. aeruginosa causes microglia and astrocyte activation, blood-brain barrier breakdown, and tau pathology in wild-type mice 24 hours post-infection. At lower doses of P. aeruginosa, I have seen microglia activation but no blood-brain barrier dysfunction. Microglia can influence blood-brain barrier breakdown and tau pathology as

well as regulate neuroimmune pathways. Taken together, this has led to the hypothesis that pneumonia first causes microglia activation, leading to blood-brain barrier breakdown, and tau phosphorylation in the brain. Using a quadruple labeled mouse model (PrismPlus), I will image longitudinally from just 3 hours post-infection to

elucidate the temporal resolution and mechanisms of neurovascular unit dysfunction in the brain. I will also assess neurovascular unit dysfunction in matched pneumonia vs. non-pneumonia post-mortem brain and lung tissue. This project will be the first step towards developing novel and effective therapies to protect neurovascular

function in patients with severe lung infections, while allowing me to master the amazing technique of multiphoton imaging of mouse brain through a cranial window. Migraine disorders have a global prevalence of approximately 15% and are the third highest cause of disability-adjusted life years. However, much is still unknown about the

pathology of migraines, particularly at the capillary level, and more effective treatments are needed. For the K00 phase, I will utilize my mastery of intravital imaging of the neurovascular unit at the capillary level, to investigate neurovascular and neuroimmune mechanisms in migraine mouse models.