GPR4 in blood brain barrier dysfunction in brain ischemia

摘要 阿尔茨海默病和相关痴呆(ADRD)是一种多因素疾病。为了有效地治疗ADRD， 更好地了解导致疾病病因的各种因素是重要的。近年来，有 认知损害和痴呆(VCID)患者对血管贡献的认识增加 ADRD的发展和进展。虽然之前的研究已经检查了多种机制 导致血管功能障碍的原因是，细胞外pH在这一过程中的重要作用知之甚少 进程。然而，功能磁共振成像显示，脑酸中毒不仅发生在痴呆症患者中，而且 与疾病严重程度也呈正相关。在我们的初步研究中，我们进一步表明，5XFAD 痴呆小鼠模型表现为慢性脑酸中毒。此外，脑部酸中毒突出且持续存在。 在脑缺血和创伤性脑损伤后，这容易在以后的生活中发展为痴呆症。在……里面 与这些情况下大脑pH值下降的普遍情况相比，对脑酸的了解很少 血管性痴呆症的信号传导。为了填补这一知识空白，这一补充申请将采取独特的 角度和焦点是酸(质子)通过GPR4介导的信号转导，GPR4是一种质子敏感的GPCR 脑微血管内皮细胞(BMEC)。利用5XFAD小鼠和一种新的条件性GPR4 基因敲除小鼠，这一应用将确定内皮细胞中GPR4的遗传消融是否缓解 5XFAD痴呆小鼠模型中的认知障碍和神经炎症。产生更多洞察力 对于痴呆症和大脑pH值，这项应用将确定5XFAD中大脑pH值随年龄的变化 老鼠。此外，这项应用程序将进一步研究观察到的变化背后的分子信号和 对分离自5XFAD动物的BMEC细胞进行无偏转录组分析。结果是 所获得的结果将为今后针对这一目标的深入机制以及翻译研究奠定基础 ADRD中的新途径。

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.