Role of the tPA/plasmin System in Alzheimers Disease

描述（由申请人提供）：该提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，一种与淀粉样蛋白-β（A-β）肽清除有关的蛋白水解系统，是研究开发可能的阿尔茨海默病（AD）治疗剂的重要途径。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，损害循环系统的疾病是AD发展的危险因素，并暗示AD具有脑血管成分。本研究的目的是研究tPA/plg系统在过表达淀粉样β前体蛋白（A-betaPP）的转基因小鼠中AD样病理学进展中的作用。由于纤溶酶原激活物抑制剂-1（PAI-1）的表达，tPA/plg系统活性在AD转基因小鼠和患有AD的个体中被抑制，PAI-1是一种在炎症期间过表达的蛋白质，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，我们计划研究在C57/BI 6背景下A-β PP转基因小鼠中tPA、plg或PA 1 -1表达丧失的影响。其次，我们计划研究纤维蛋白沉积在加重AD病理和脑血管功能障碍中的作用。第三，我们计划鉴定阻断PAI-1和tPA相互作用的新化合物，并测试这些化合物，沿着已知的PAI-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，用于开发针对tPA/纤溶酶级联的可能的治疗干预策略，以对抗AD进展

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