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

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年将大幅增加到800万。目前，FDA批准用于治疗阿尔茨海默病的少数药物仅显示出在较短时间内改善临床症状的适度效果，而且没有一种药物显示出对疾病进展的明显影响。迫切需要新的治疗方法。在这个项目中，我们假设一个新的靶点，激活/改变血管内皮治疗干预阿尔茨海默病。我们实验室的研究表明，AD患者的大脑微循环功能失调，其特征是多种炎症蛋白和神经毒性因子的上调。这些血管源性因子中有许多对神经元具有直接伤害或致死作用。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，进而释放活性氧和炎症因子，从而传播有害的神经炎症。“激活”的脑血管系统代表了阿尔茨海默病大脑中一个重要的、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患者的认知功能。如果认为血管源性因素导致了阿尔茨海默症患者大脑中的一系列事件，进而导致痴呆，那么阻断或减少血管激活，以及随后释放神经毒性因素，应该会改善认知能力。这一假设是新颖的，可检验的，并有初步数据支持。为了验证这一假设，我们提出以下具体目的：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阿尔茨海默病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，以确定给药是否会改变认知衰退的发生和/或严重程度。认知功能评估采用桡臂和水迷宫行为分析。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中神经毒性和炎症蛋白的表达。显示血管活化表型与认知障碍之间因果关系的数据可能为阿尔茨海默病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被FDA批准或用于癌症治疗的III期临床试验，因此这些药物的新临床试验可以在AD患者中快速设计和实施。

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. PUBLIC HEALTH RELEVANCE: New therapeutic approaches for Alzheimer's disease (AD) are desperately needed. In this project we propose brain blood vessels as new targets for therapeutic intervention in AD. 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 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 b rapidly designed and implemented in AD patients.