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.

项目概要/摘要 随着我们预期寿命的延长，人口老龄化的迅速扩大带来了 痴呆症的患病率，包括阿尔茨海默病（AD）和血管性认知障碍（VCI）。 目前尚无神经保护药物可用于治疗 AD 和 VCI 患者。 常见类型的痴呆症，给人们带来巨大的社会经济负担以及破坏性影响 这两种形式的痴呆症的特征都是患者及其护理人员的生活状况恶化。 形成血脑屏障（BBB）的神经血管单位，在许多情况下甚至先于血脑屏障的发生 然而不幸的是，AD 和 VCI 中 BBB 恶化的机制尚不清楚。 因此，没有任何疗法可以保护血脑屏障，在我的论文中，我已经确定前列腺素。 降解酶 15-羟基前列腺素脱氢酶 (15-PGDH) 在两者中病理性升高 我还表明，人类 AD 和 VCI 患者大脑中的 15-PGDH 酶活性是 在 AD 的 5xFAD 小鼠模型以及正常衰老中，这种现象均有所增加。 5xFAD 小鼠中 15-PGDH 的药理和遗传抑制显示出针对 BBB 的强大保护作用 恶化和其他 AD 相关病理，包括认知缺陷、神经发生和轴突受损 与β淀粉样蛋白病理学无关的变性，我还发现了前列腺素的变性。 在 5xFAD 小鼠中，D2 (PGD2) 在大脑中通过 15-PGDH 抑制而显着升高。 PGD​​2 负责 15-PGDH 抑制介导的 BBB 保护，这是 在我提案的 F99 部分，我将评估是否与改善内皮细胞屏障功能有关。 15-PGDH 抑制还可以防止我将使用的 VCI 高脂肪饮食小鼠模型中的 BBB 恶化。 创新的 2 光子显微镜体内成像和电子显微镜确定 BBB 的轨迹 恶化，以及测试15-PGDH抑制的保护功效我还将确定是否PGD2。 介导体内和体外的保护作用，正如之前的文献表明 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。 成华博士大脑中血管周围巨噬细胞（PVM）与内皮细胞之间的相互作用 Gu 的实验室将利用创新的 cre 重组酶系统来专门针对大脑中的 PVM。 研究 PVM 中葡萄糖代谢的改变以及 PVM 和内皮细胞的转录组分析， 然后，我将测试 PVM 中代谢的改变如何与 AD 相关的风险因素相互作用。 内皮细胞启动 BBB 恶化的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相关病理恶化，这将有助于发现和 为患有 AD 和 VCI 的患者开发新的神经保护方法。