Targeting vascular activation: a novel therapeutic strategy for Alzheimer's

靶向血管激活：阿尔茨海默病的新型治疗策略

• 批准号: 8450103
• 负责人: PAULA GRAMMAS
• 金额: $ 17.54万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450103
• 关键词: Affect; Age-Months; Alzheimer' s Disease; Angiopoietin-2; Animal Model; Behavioral Assay; Blood; Blood Vessels; Brain; Cerebrum; Clinical; Clinical Trials; Cognitive; Data; Dementia; Development; Disease Progression; Enzyme-Linked Immunosorbent Assay; Event; FDA approved; Impaired cognition; Inflammatory; Interleukin-6; Interleukin-8; Interleukins; Interstitial Collagenase; Intervention; Laboratories; Lead; Link; Microcirculation; Monocyte Chemoattractant Protein-1; Mus; Neurodegenerative Disorders; Neuroglia; Neurons; Neurotoxins; Nitric Oxide; Pathologic; Patients; Performance; Pharmaceutical Preparations; Phase III Clinical Trials; Phenotype; Physiological; Proteins; Radial; Reactive Oxygen Species; Severities; Source; Symptoms; Testing; Therapeutic Intervention; Thrombin; Transforming Growth Factors; Transgenic Organisms; Tumor Necrosis Factor-alpha; United States; Up-Regulation; Vascular Endothelial Growth Factors; Vascular Endothelium; Work; arm; cancer therapy; cognitive function; design; hypoxia inducible factor 1; improved; inhibitor/antagonist; injured; insight; neuroinflammation; neuron loss; neurotoxic; novel; novel therapeutic intervention; novel therapeutics

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive, irreversible, neurodegenerative disease that affects more than 5 million people in the United States. This number is a 10 percent increase from the previous estimate of 4.5 million and is projected to sharply increase to 8 million by 2030. At present, the few agents that are FDA- approved for treatment of AD have demonstrated only modest effects in modifying clinical symptoms for relatively short periods and none has shown a clear effect on disease progression. New therapeutic approaches are desperately needed. In this project we postulate a new target for therapeutic intervention in AD, the activated/altered vascular endothelium. Work from our laboratory has demonstrated a dysfunctional cerebral microcirculation in AD characterized by the upregulation of numerous inflammatory proteins and neurotoxic factors. Many of these vascular-derived factors are directly injurious to or lethal for neurons. Vascular-derived factors can also injure neurons indirectly by activating neighboring glial cells which in turn release reactive oxygen species and inflammatory factors thus propagating deleterious neuroinflammation. The "activated" brain vasculature represents an important and unexplored source of neurotoxins in the AD brain. It is our hypothesis that pharmacologic interventions aimed at reducing vascular activation and release of neurotoxins will improve cognitive function in AD. If the notion that vascular-derived factors contribute to a cascade of events in the AD brain that lead to dementia then blocking or decreasing vascular activation, and the subsequent release of neurotoxic factors, should improve cognitive performance. This hypothesis is novel, testable and supported by preliminary data. To test this hypothesis we propose the following Specific Aim: To determine whether pharmacologic interventions aimed at reducing vascular activation and release of neurotoxins improve cognitive function in an animal model of AD. Transgenic AD mice receive drugs beginning at 2 or 10 months of age and continuing for 6 months. The performance of cognitive tasks is compared between AD mice and drug-treated AD mice to determine whether administration of drug alters the onset and/or severity of cognitive decline. Cognitive function is assessed using radial arm and watermaze behavioral assays. In addition, expression of neurotoxic and inflammatory proteins is determined in the blood and CSF by ELISA and in the cerebrovasculature by immunostaining. Data demonstrating a causal link between the activated vascular phenotype and cognitive impairment could provide valuable new insights into the development of AD. Furthermore, because several vascular activation inhibitor drugs are currently FDA approved or in use in Phase III clinical trials for cancer treatment, new clinical trials with these drugs could be rapidly designed and implemented in AD patients.

描述（由申请人提供）：阿尔茨海默病（AD）是一种进行性、不可逆的神经退行性疾病，在美国影响超过500万人。这一数字比之前估计的450万增加了10%，预计到2030年将急剧增加到800万。目前，FDA批准用于治疗AD的少数药物在相对短的时间内仅表现出适度的改善临床症状的作用，并且没有一种药物显示出对疾病进展的明显作用。迫切需要新的治疗方法。在这个项目中，我们假设一个新的目标，在AD的治疗干预，激活/改变血管内皮。我们实验室的工作已经证明了AD的脑微循环功能障碍，其特征在于许多炎症蛋白和神经毒性因子的上调。这些血管源性因子中的许多对神经元直接有害或致命。血管源性因子也可以通过激活邻近的神经胶质细胞间接损伤神经元，神经胶质细胞反过来释放活性氧和炎症因子，从而传播有害的神经炎症。“活化的”脑血管系统代表AD脑中神经毒素的重要且未探索的来源。我们的假设是，旨在减少血管激活和神经毒素释放的药物干预将改善AD的认知功能。如果血管源性因素有助于AD大脑中导致痴呆的级联事件的概念，那么阻断或减少血管激活以及随后释放的神经毒性因子应该会改善认知能力。这一假设是新颖的，可检验的，并得到初步数据的支持。为了验证这一假设，我们提出了以下具体目标：以确定是否旨在减少血管激活和神经毒素释放的药物干预改善AD动物模型的认知功能。转基因AD小鼠在2或10个月大时开始接受药物治疗，并持续6个月。在AD小鼠和药物治疗的AD小鼠之间比较认知任务的表现，以确定药物的施用是否改变认知下降的发作和/或严重程度。认知功能使用径向臂和水迷宫行为测定法进行评估。此外，通过ELISA测定血液和CSF中神经毒性和炎性蛋白的表达，并通过免疫染色测定血管系统中神经毒性和炎性蛋白的表达。显示激活的血管表型和认知障碍之间存在因果关系的数据可以为AD的发展提供有价值的新见解。此外，由于几种血管活化抑制剂药物目前已获得FDA批准或用于癌症治疗的III期临床试验，因此可以在AD患者中快速设计和实施这些药物的新临床试验。