Role of the tPA/plasmin System in Alzheimers Disease

tPA/纤溶酶系统在阿尔茨海默病中的作用

• 批准号: 7112914
• 负责人: SIDNEY STRICKLAND
• 金额: $ 38.16万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-25 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7112914
• 关键词: Alzheimer' s disease; amyloid proteins; disease /disorder model; fibrin; genetically modified animals; laboratory mouse; neuropharmacology; pathologic process; plasmin; plasminogen activator; plasminogen activator inhibitors

DESCRIPTION (provided by applicant): The overall hypothesis of this proposal is that the tissue plasminogen activator/plasminogen (tPA/plg) fibrinolytic cascade, a proteolytic system which has been implicated in the clearance of amyloid-beta (A-beta) peptide, is an important pathway to investigate for developing possible therapeutic agents against Alzheimer's disease (AD). The abnormal deposition of A-beta in the parenchyma and blood vessels of the brain is a pathological hallmark of AD, the most common cause of dementia and cognitive decline in the aged. Additionally, epidemiological studies indicate that diseases that compromise the circulatory system are risk factors for the development of AD, and imply that AD has a cerebrovascular component. The objectives of this proposal are to investigate the role of the tPA/plg system in the progression of AD-like pathology in transgenic mice overexpressing the amyloid-beta precursor protein (A-betaPP). The tPA/plg system activity is depressed in AD transgenic mice and in individuals with AD, due to the expression of plasminogen activator inhibitor-1 (PAl-l), a protein overexpressed during inflammation, commonly seen in AD. To accomplish this goal, we propose three specific aims. First, we plan to investigate the effects of the loss of tPA, plg, or PAl-1 expression in A-betaPP transgenic mice in a C57/BI6 background. Second, we plan to investigate the role of fibrin deposition in exacerbating the pathology and cerebrovascular dysfunction in AD. Third, we plan to identify new compounds that block the interaction of PAl-1 and tPA, and to test these, along with known PAl-1 inhibitors, for their effects in AD mouse models. These experiments will take advantage of transgenic and knockout mouse lines as in vivo paradigms for the development of possible therapeutic intervention strategies, targeting the tPA/plasmin cascade, against AD progression

描述(申请人提供)：这项建议的总体假设是，组织纤溶酶原激活物/纤溶酶原(tPA/PLG)纤溶级联反应是研究开发可能的阿尔茨海默病(AD)治疗药物的重要途径。A-β在脑实质和血管中的异常沉积是AD的病理标志，AD是老年人痴呆和认知能力下降的最常见原因。此外，流行病学研究表明，危害循环系统的疾病是阿尔茨海默病发生的危险因素，并暗示阿尔茨海默病有脑血管成分。本研究的目的是研究tPA/PLG系统在过量表达淀粉样β前体蛋白(A-βPP)转基因小鼠的AD样病理进展中的作用。在AD转基因小鼠和AD患者中，由于纤溶酶原激活物抑制物-1(PAL-L)的表达，tPA/PLG系统的活性受到抑制。纤溶酶原激活物抑制物-1是一种在炎症过程中过度表达的蛋白质，在AD中常见。为了实现这一目标，我们提出了三个具体目标。首先，我们计划在C57/BI6背景下研究tPA、PLG或PAL-1表达缺失对A-BetaPP转基因小鼠的影响。第二，我们计划研究纤维蛋白沉积在加重AD的病理和脑血管功能障碍中的作用。第三，我们计划确定阻断PAL-1和tPA相互作用的新化合物，并测试这些化合物以及已知的PAL-1抑制剂在AD小鼠模型中的作用。这些实验将利用转基因和基因敲除小鼠品系作为体内范例，开发可能的治疗干预策略，针对tPA/纤溶酶级联反应，对抗AD进展