Discovering Novel Mechanisms and Treatment for Aging-Related Dementia: Probing Medin and Abeta Vasculopathy

发现衰老相关痴呆的新机制和治疗方法：探索 Medin 和 Abeta 血管病

• 批准号: 10359074
• 负责人: Raymond Quezon Migrino
• 金额: --
• 依托单位: PHOENIX VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359074
• 关键词: 3-Dimensional; Adjuvant Therapy; Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Antioxidants; Astrocytes; Autopsy; Biochemistry; Biological; Biology; Biomedical Engineering; Blood Vessels; Brain; Brain Injuries; Cardiovascular system; Cell Survival; Cells; Cerebrovascular Disorders; Clinical; Cognition; Cognitive; Coupling; Data; Dementia; Development; Diabetes Mellitus; Encephalitis; Endothelial Cells; Endothelium; Exposure to; Functional disorder; General Population; Glucose; Goals; Health Care Costs; Healthcare; Human; Hyperlipidemia; Hypoxia; Hypoxic Brain Damage; Impaired cognition; Inflammation; Inflammatory; Injury; Intervention; Investigation; Ischemia; Ischemic Stroke; Lead; Learning; Link; Lipids; Maintenance; Metabolic; Middle Cerebral Artery Occlusion; Modeling; Molecular; Molecular Probes; Mus; Nerve Degeneration; Neurons; Oxidative Stress; Palmitic Acids; Patients; Phospholipids; Play; Process; Proteins; Reperfusion Injury; Reperfusion Therapy; Role; Signal Transduction; Stress; Stroke; Testing; Tissue Donors; Tissue Model; Vascular Dementia; Vascular Diseases; Veterans; base; blood-brain barrier function; brain cell; brain endothelial cell; brain tissue; cardiovascular risk factor; cerebral artery; cerebrovascular; disability; disorder control; efficacy testing; endothelial dysfunction; human tissue; in vivo; medin; military veteran; molecular targeted therapies; mortality; multidisciplinary; nanoliposome; nanoscience; neuroinflammation; neuropathology; neurosurgery; neurotransmission; neurovascular unit; novel; novel therapeutics; nuclear factor-erythroid 2; organ on a chip; particle; prevent; relating to nervous system; sialogangliosides; stroke model; vascular cognitive impairment and dementia; vascular inflammation

Abstract Vascular dementia (VaD) is the second most common cause of dementia overall and the most common in patients < 74 years old. In an aging veteran population, dementia is a critical health care issue that affects 7.3% of veterans ≥ 65 years old1. To prevent or manage VaD, it is critical to understand its early pathophysiology, specifically learning how vascular disease and inflammation, a process that occurs decades before VaD, modulate neuroinflammation and neurodegeneration. We have identified and characterized a novel putative agent for vascular aging, medin, one of the most common human amyloid proteins, found in greater quantities in VaD and Alzheimer's disease (AD) patients, and which can cause endothelial dysfunction, pro-inflammatory activation similar to cardiovascular risk factors (CVRFs), as well as exacerbate hypoxic injury to endothelial cells (ECs). In later stages of vascular disease, atherosclerotic and thromboembolic changes can lead to ischemia and brain tissue hypoxia or stroke, the 5th major cause of mortality. Investigating factors, such as medin, that could potentially exacerbate this injury would lead to new treatment targets. Additionally, we showed that monosialoganglioside-containing nanoliposomes (NLGM1, phospholipid particles <100 nm) protect against hypoxia and oxidative stress-induced endothelial dysfunction and vascular inflammation. Based on these initial discoveries, our overall goal is to investigate how the aging vasculature influences neural inflammation and function and identify novel treatment targets and intervention to mitigate hypoxic injury in VaD. In Aim 1 we will establish mechanisms by which cerebrovascular inflammation modulates neuroinflammation and neurodegeneration. Here we will use 2D cell, novel 3D vascularized brain organ-on-a-chip and isolated ex-vivo collateral cerebral arteries from brain donors with VaD, AD or normal cognition to determine how vascular inflammation induced by medin or CVRFs modulate astrocyte and microglial inflammation and affect neuronal function and viability. In Aim 2, we will establish the role of medin in modulating hypoxic neurovascular unit injury. We will also test whether NLGM1 could protect against hypoxic injury to cellular components of the neurovascular unit using the 3D chip model and perform pilot investigation to test whether NLGM1 can protect mice against hypoxic injury from middle cerebral artery occlusion. Using novel cellular and human tissue models developed by our group, the proposal could impact our fundamental understanding of the early genesis of VaD, identify and characterize medin as a novel treatment target and validate NLGM1 as a novel therapeutic option.

抽象的 血管性痴呆 (VaD) 是痴呆症的第二大常见原因，也是最常见的痴呆症 < 74 岁的患者。在老龄化退伍军人群体中，痴呆症是一个严重的医疗保健问题，影响 7.3% 的退伍军人年龄≥ 65 岁1。为了预防或治疗 VaD，了解其早期病理生理学至关重要， 特别是了解血管疾病和炎症（这一过程发生在 VaD 之前几十年）如何 调节神经炎症和神经变性。我们已经确定并描述了一个新颖的假设 血管老化剂 medin，是最常见的人类淀粉样蛋白之一，含量较高 在 VaD 和阿尔茨海默氏病 (AD) 患者中，可能会导致内皮功能障碍、促炎 类似于心血管危险因素（CVRF）的激活，并加剧内皮细胞的缺氧损伤 （EC）。在血管疾病的后期，动脉粥样硬化和血栓栓塞变化可导致缺血 脑组织缺氧或中风是第五大死亡原因。调查因素，例如药物， 可能会加剧这种损伤，从而产生新的治疗目标。此外，我们还表明 含有单唾液酸神经节苷脂的纳米脂质体（NLGM1，磷脂颗粒<100 nm）可防止 缺氧和氧化应激引起的内皮功能障碍和血管炎症。基于这些初步 发现，我们的总体目标是研究老化的脉管系统如何影响神经炎症和 功能并确定新的治疗目标和干预措施，以减轻 VaD 的缺氧损伤。在目标 1 中，我们将 建立脑血管炎症调节神经炎症的机制 神经变性。在这里，我们将使用 2D 细胞、新型 3D 血管化脑器官芯片和离体离体 来自患有 VaD、AD 或正常认知的脑供体的侧脑动脉，以确定血管如何 Medin 或 CVRF 诱导的炎症调节星形胶质细胞和小胶质细胞炎症并影响神经元 功能和生存能力。在目标 2 中，我们将确定 medin 在调节缺氧神经血管单元中的作用 受伤。我们还将测试 NLGM1 是否可以保护细胞成分免受缺氧损伤 使用3D芯片模型构建神经血管单元并进行初步研究以测试NLGM1是否可以保护 小鼠对抗大脑中动脉闭塞引起的缺氧损伤。使用新型细胞和人体组织模型 由我们小组开发，该提案可能会影响我们对 VaD 早期起源的基本理解， 识别并表征 medin 作为一种新的治疗靶点，并验证 NLGM1 作为一种新的治疗选择。