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）：阿尔茨海默氏病 (AD) 是一种进行性、不可逆转的神经退行性疾病，影响着超过 500 万人在美国。这个数字比之前估计的 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 的少数药物仅在相对较短的时间内显示出在改变临床症状方面的有限效果，并且没有一种药物对疾病进展显示出明显的效果。迫切需要新的治疗方法。在这个项目中，我们提出了 AD 治疗干预的新目标，即激活/改变的血管内皮。我们实验室的工作表明，AD 患者的大脑微循环功能失调，其特征是大量炎症蛋白和神经毒性因子的上调。许多血管源性因子直接损伤或致命神经元。血管源性因子还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。 “激活的”脑脉管系统是 AD 脑中神经毒素的一个重要且未经探索的来源。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。如果血管源性因素导致 AD 大脑中一系列事件导致痴呆，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。这个假设是新颖的、可测试的并且有初步数据的支持。为了检验这一假设，我们提出以下具体目标：确定旨在减少血管活化和神经毒素释放的药物干预是否可以改善 AD 动物模型的认知功能。转基因 AD 小鼠从 2 个月或 10 个月大时开始接受药物治疗，持续 6 个月。比较 AD 小鼠和药物治疗的 AD 小鼠的认知任务表现，以确定药物的施用是否会改变认知衰退的发作和/或严重程度。使用桡臂和水迷宫行为测定来评估认知功能。此外，通过 ELISA 测定血液和脑脊液中神经毒性和炎症蛋白的表达，通过免疫染色测定脑血管系统中神经毒性和炎症蛋白的表达。证明激活的血管表型与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，由于几种血管激活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使用这些药物的新临床试验。