GPR4 in blood brain barrier dysfunction in brain ischemia

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ABSTRACT Alzheimer’s disease and related dementias (ADRD) are multifactorial diseases. For efficient treatment of ADRD, a better understanding of various factors leading to disease etiology is important. In recent years, there are increased appreciation of vascular contributions to cognitive impairment and dementia (VCID) in the development and progression of ADRD. While previous studies have examined multiple mechanisms contributing to vascular dysfunction, little is known about the functional important of extracellular pH in this process. However, functional MRI imaging shows that brain acidosis not only occurs in dementia patients but also exhibits positive correlation with disease severity. In our preliminary study, we further showed that a 5XFAD mouse model of dementia exhibited chronic brain acidosis. In addition, brain acidosis is prominent and persistent following ischemia and traumatic brain injury, which predispose the development of dementia later in life. In contrast to the prevalence of brain pH reduction in these conditions, there is a dearth of knowledge on brain acid signaling in vascular dementia. To fill in this gap in knowledge, this Supplement application will take a unique angle and focus on acid (proton)-mediated signaling through GPR4, a proton-sensitive GPCR which is present in brain microvascular endothelial cells (BMEC). Using the 5XFAD mouse and a novel conditional GPR4 knockout mouse, this application will determine whether genetic ablation of GPR4 in endothelium alleviates cognitive impairment and neuroinflammation in the 5XFAD mouse model of dementia. To generate more insights into dementia and brain pH, this application will determine age-dependent changes in brain pH in the 5XFAD mice. Further, this application will further investigate molecular signaling underlying the observed changes and perform an unbiased transcriptome analysis in BMEC cells isolated from the 5XFAD animals. The results obtained will lay the groundwork for future in-depth mechanistic as well as translational studies of targeting this novel pathway in ADRD.