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

血管性认知障碍和阿尔茨海默病血脑屏障恶化的机制

• 批准号: 10728931
• 负责人: Yeojung Koh
• 金额: $ 4.92万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-11 至 2025-09-10
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728931
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid; Animal Model; Area; Biology; Blood - brain barrier anatomy; Blood Vessels; Brain; Caregivers; Cell Communication; Cognitive deficits; Communication; Creativeness; Data; Dementia; Deterioration; Development; Economic Burden; Electron Microscopy; Endothelial Cells; Enterobacteria phage P1 Cre recombinase; Enzymes; Experimental Designs; Foundations; Future; Gene Expression Profile; Genetic; Glycolysis; Goals; Health; High Fat Diet; Hippocampus; Human; Image; Immune; Immune system; Immunology; Impairment; In Vitro; Inflammatory; International; Laboratories; Learning; Life; Literature; Longevity; Macrophage; Mediating; Medical; Medical Research; Medicine; Mentorship; Metabolic; Metabolism; Microglia; Modeling; Mus; Nerve Degeneration; Neurobehavioral Manifestations; Neurosciences Research; Oxidoreductase; Pathologic; Pathology; Patients; Peripheral; Phase; Postdoctoral Fellow; Prevalence; Process; Prostaglandin D2; Prostaglandins; Research; Research Activity; Research Project Grants; Risk Factors; Rodent Model; Role; Scientist; Senile Plaques; System; Testing; Thinking; Time; Transcript; Treatment Efficacy; United States; Vascular Cognitive Impairment; Vascular Dementia; Vascular System; Work; aging population; axonal degeneration; beta amyloid pathology; brain endothelial cell; brain health; career; cost; effective therapy; efficacy evaluation; glucose metabolism; improved; in vivo; in vivo Model; in vivo imaging; innovation; insight; interest; medical schools; mouse model; neurogenesis; neuroprotection; neurovascular; neurovascular unit; new therapeutic target; normal aging; novel; pharmacologic; post-doctoral training; preservation; prevent; protective effect; protective efficacy; research study; skills; socioeconomics; symposium; transcriptomic profiling; two photon microscopy; two-photon

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.

项目摘要/摘要 随着我们预期寿命的增加，快速增长的老龄化人口带来了 痴呆症患病率，包括阿尔茨海默病(AD)和血管认知障碍(VCI)。然而， 目前还没有治疗这些疾病的神经保护性药物。AD和VCI是最多的 常见类型的痴呆症，并造成巨大的社会经济负担以及对 病人及其照顾者的生命。这两种形式的痴呆症的特征都是 形成血脑屏障(BBB)的神经血管单位，在许多情况下甚至在发病之前 认知缺陷。然而，不幸的是，AD和VCI中血脑屏障恶化的机制尚不清楚。AS 因此，目前还没有保护血脑屏障的疗法。在我的论文工作中，我已经确定前列腺素 降解酶15-羟基前列腺素脱氢酶(15-PGDH)在这两种疾病中均呈病理性升高 人类AD和VCI在人类患者中的分布。我还证明了15-PGDH在大脑中的酶活性是 在AD的5xFAD小鼠模型中增加，以及正常衰老。重要的是，我已经确定 药理和遗传抑制对5xFAD小鼠血脑屏障的保护作用 退化和其他与AD相关的病理，包括认知障碍、神经发生受损和轴突 变性，独立于淀粉样蛋白β病理。我还发现在前列腺素中，前列腺素 在5xFAD小鼠中，通过抑制15-PGDH，D2(PGD2)在大脑中最显著地升高。因此，我 假设PGD2负责15-PGDH抑制介导的血脑屏障保护，并且这是 与改善内皮细胞屏障功能有关。在我的提案的F99部分，我将评估是否 在高脂饮食的VCI小鼠模型中，抑制15-PGDH也可以保护BBB的恶化。我会利用 创新的双光子显微镜活体成像和电子显微镜确定血脑屏障的轨迹 并检测15-前列腺素脱氢酶抑制的保护效果。我还会确定PGD2是否 介导体内和体外的保护作用，正如先前的文献所表明的那样，PGD2在 增强内皮细胞屏障功能。在K00阶段，我将通过调查来扩展我的BBB研究 成华博士脑部血管周围巨噬细胞与血管内皮细胞的相互作用 顾的实验室。我将利用一种创新的重组酶系统来特别针对大脑中的PVM和 研究PVM中葡萄糖代谢的变化以及PVM和内皮细胞中的转录图谱， 作为AD相关风险因素的函数。然后，我将测试PVM中这种改变的新陈代谢是如何与 内皮细胞启动血脑屏障恶化。这项研究的成功完成将提供新的视角 血脑屏障如何随着衰老和痴呆症相关的病理而恶化，这将使这一发现和 为AD和VCI患者开发新的神经保护方法。