Mechanisms of blood-brain barrier deterioration in vascular cognitive impairment and Alzheimers disease

Project Summary/Abstract With our expected lifespans increasing, the rapidly expanding aging population is bringing an increased prevalence of dementia, including Alzheimer’s disease (AD) and vascular cognitive impairment (VCI). However, there are still no neuroprotective medicines for treating patients with these conditions. AD and VCI are the most common types of dementia and impose a huge socioeconomic burden as well as devastating impacts on the lives of patients and their caregivers. Both of these forms of dementia are characterized by deterioration of the neurovascular unit that forms the blood-brain barrier (BBB), which in many cases even precedes the onset of cognitive deficits. Unfortunately, however, the mechanisms of BBB deterioration in AD and VCI are unclear. As a result, there are no therapies to protect the BBB. In my thesis work, I have established that the prostaglandin degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is pathologically elevated in both human AD and VCI in human patients. I have also shown that the enzymatic activity of 15-PGDH in the brain is increased in the 5xFAD mouse model of AD, as well as normal aging. Importantly, I have established that pharmacologic and genetic inhibition of 15-PGDH in 5xFAD mice shows robust protection against BBB deterioration and other AD-related pathology, including cognitive deficits, impaired neurogenesis, and axon degeneration, independently of amyloid β pathology. I have also found that of the prostaglandins, prostaglandin D2 (PGD2) is most prominently elevated in the brain by 15-PGDH inhibition in 5xFAD mice. Therefore, I hypothesize that PGD2 is responsible for 15-PGDH inhibition-mediated protection of the BBB, and that this is related to improved endothelial cell barrier function. During the F99 portion of my proposal, I will evaluate whether 15-PGDH inhibition also protects from BBB deterioration in the high fat diet mouse model of VCI. I will utilize innovative 2-photon microscopy in vivo imaging and electron microscopy to determine the trajectory of BBB deterioration, as well as test the protective efficacy of 15-PGDH inhibition. I will also determine whether PGD2 mediates the protective effect both in vivo and in vitro, as previous literature suggests a role of PGD2 in increasing endothelial cell barrier function. During the K00 phase, I will expand my BBB research by investigating the interaction between perivascular macrophages (PVMs) and endothelial cells in the brain in Dr. Chenghua Gu’s laboratory. I will utilize an innovative cre-recombinase system to specifically target PVMs in the brain and investigate altered glucose metabolism in PVMs and transcriptomic profiling in both PVMs and endothelial cells, as a function of AD-related risk factors. Then, I will test how this altered metabolism in PVMs interacts with endothelial cells to initiate BBB deterioration. Successful completion of this study will provide new perspectives of how the BBB deteriorates with aging and dementia-related pathology, which will enable the discovery and development of new neuroprotective approaches for patients suffering from AD and VCI.