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(申请人提供)：阿尔茨海默病(AD)是一种进行性的、不可逆转的神经退行性疾病，在美国有500多万人受到影响。这一数字比之前估计的450万增加了10%，预计到2030年将大幅增加到800万。目前，FDA批准用于治疗AD的少数药物在相对较短的时间内仅显示出适度的改善临床症状的效果，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，我们假设了AD治疗干预的一个新靶点，激活/改变的血管内皮细胞。我们实验室的研究表明，阿尔茨海默病患者的大脑微循环功能障碍，其特征是大量炎性蛋白和神经毒性因子上调。这些血管衍生因子中的许多对神经元都是直接损伤或致命的。血管衍生因子还可以通过激活邻近的神经胶质细胞来间接损伤神经元，神经胶质细胞进而释放活性氧和炎症因子，从而传播有害的神经炎症。这种“激活的”脑血管系统是AD大脑中一种重要的、未被探索的神经毒素来源。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。如果认为血管衍生因子导致AD大脑中的一系列事件导致痴呆，那么阻止或减少血管激活，以及随后神经毒性因子的释放，应该会改善认知能力。这一假设是新颖的、可检验的，并得到了初步数据的支持。为了验证这一假设，我们提出了以下具体目标：确定旨在减少血管激活和神经毒素释放的药物干预是否能改善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，以确定给药是否改变认知功能下降的开始和/或严重程度。认知功能的评估使用放射臂和水迷宫行为分析。此外，神经毒性和炎性蛋白在血液和脑脊液中的表达通过ELISA检测，在脑血管中的表达通过免疫染色来检测。证明激活的血管表型和认知损害之间的因果联系的数据可以为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药目前已获得FDA批准或用于癌症治疗的第三阶段临床试验，这些药物的新临床试验可能会迅速设计并在AD患者中实施。