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.

项目总结/摘要 随着我们预期寿命的增加，迅速扩大的老龄化人口正在增加 痴呆的患病率，包括阿尔茨海默病（AD）和血管性认知障碍（VCI）。然而，在这方面， 仍然没有治疗患有这些病症的患者的神经保护药物。AD和VCI是最常见的 常见类型的痴呆症，并造成巨大的社会经济负担以及对 患者及其护理人员的生活。这两种形式的痴呆症的特点是恶化的， 血脑屏障（BBB）是形成血脑屏障（BBB）的神经血管单位，在许多情况下，血脑屏障甚至先于脑缺血发作。 认知缺陷然而，不幸的是，AD和VCI中BBB恶化的机制尚不清楚。作为 因此，没有治疗方法来保护BBB。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）在两种情况下均病理性升高， 人AD和VCI。我还表明，大脑中15-PGDH的酶活性是 在AD的5xFAD小鼠模型以及正常衰老中增加。重要的是，我已经确定， 在5xFAD小鼠中，15-PGDH的药理学和遗传抑制显示出对BBB的稳健保护作用 恶化和其他AD相关病理，包括认知缺陷、神经发生和轴突损伤 变性，独立于淀粉样蛋白β病理学。我还发现前列腺素中，前列腺素 在5xFAD小鼠中，通过15-PGDH抑制，脑中的D2（PGD 2）最显著升高。所以我 假设PGD 2负责15-PGDH抑制介导的BBB保护，并且这是 与改善内皮细胞屏障功能有关。在我的建议的F99部分，我将评估是否 15-PGDH抑制还在VCI的高脂肪饮食小鼠模型中保护BBB恶化。我会利用 创新的双光子显微镜在体内成像和电子显微镜，以确定BBB的轨迹 恶化，以及测试15-PGDH抑制的保护功效。我还将确定PGD 2是否 介导体内和体外的保护作用，因为先前的文献表明PGD 2在 增加内皮细胞屏障功能。在K 00阶段，我将通过调查 成华博士脑内血管周围巨噬细胞（PVM）与内皮细胞的相互作用 顾的实验室。我将利用一种创新的cre重组酶系统，专门针对大脑中的PVM， 研究PVM中葡萄糖代谢改变以及PVM和内皮细胞中的转录组学谱， 作为AD相关风险因素的函数。然后，我将测试PVM中这种改变的代谢如何与 内皮细胞引发BBB恶化。这项研究的成功完成将提供新的视角 BBB是如何随着衰老和痴呆相关的病理学而恶化的，这将使我们能够发现和 为AD和VCI患者开发新的神经保护方法。