UPA Polymorphisms as a Differential Risk Factor for AD

描述（由申请人提供）：识别遗传风险因素 与阿尔茨海默病（AD）相关的疾病对于对抗阿尔茨海默病的进展至关重要。 疾病最近，几个研究小组确定了10号染色体的一个区域， 含有至少一个迟发性AD（1-3）的易感基因座， 此外，还将该区域与血浆中的 β淀粉样蛋白（AB）（1）。编码尿激酶型纤溶酶原激活剂的基因 (uPA)在这一地区的地图。此前，我们报道了uPA是 在体外和Hsiao小鼠AB模型中， 体内负荷（4）。此外，uPA将纤溶酶原转化为活性蛋白酶 纤溶酶，它降解非聚集和聚集的AB与生理 效率（初步结果和[4，5]）。AB积累是一个标志， AD，并可能导致这种疾病。综合这些数据，我们 假设10号染色体基因座之一是uPA多态性， 调节uPA促进AB清除的能力。为了评估这一点 假设，我们建议：1）评估uPA多态性在AD中的频率 并对照患者以鉴定与AD分离的多态性。在 初步工作，我们已经确定了一个uPA多态性， 与AD易感性分离。这种多态性会导致 在uPA内的位置141处的前改变，并改变uPA酶原与 聚集的纤维蛋白; 2）深入了解leu-uPA与 通过比较leu-uPA与pro-uPA纯合子个体， AD的相关临床和神经病理学标志物，包括uPA定位 在AD脑中; 3）评估leu-uPA相对于pro-uPA结合AB的能力， 体外激活纤溶酶原，抑制AB神经毒性; 4）评价 尿激酶型纤溶酶原激活剂在小鼠体内AB清除中作用 野生型或uPA基因缺陷的人。总的来说， 本文提出的方法将：1）直接评估uPA的可能作用 多态性作为AD的风险因素;和2）提供对可能的 差异uPA作用的潜在机制。这些研究 重要的是，确定其他遗传风险因素， AD将有助于早期AD诊断，从而通过以下方式促进药物发现： 在诊断前识别AD高风险患者。此外，由 评估增强对AD易感性的潜在可能机制， 这些研究可能会导致发现新的见解的分子 研究AD的潜在机制，从而提出新的治疗方法。

DESCRIPTION (provided by the applicant): Identifying genetic-risk factors associated with Alzheimers disease (AD) is critical to progress against the disease. Recently, several groups identified a region of chromosome-10 as containing at least one susceptibility locus for late-onset AD (1-3), with one group additionally associating this region with enhanced plasma levels of amyloid-Beta (AB) (1). The gene encoding urokinase-type plasminogen activator (uPA) maps within this implicated region. Previously, we reported that uPA is induced by AB-treated neurons in vitro and in the Hsiao mouse model of AB burden in vivo (4). Moreover, uPA converts plasminogen to the active protease plasmin, which degrades both non-aggregated and aggregated AB with physiologic efficiency (Preliminary Results and [4, 5]). AB accumulation is a hallmark of AD, and may be causal to this disease. Considering these data overall, we hypothesize that one of the chromosome-10 loci is an uPA polymorphism that modulates uPA's ability to contribute, to AB clearance. To assess this hypothesis, we propose to: 1) evaluate the frequency of uPA polymorphisms in AD and control patients to identify polymorphism(s) segregating with AD. In preliminary work, we have identified an uPA polymorphism that significantly segregates with AD susceptibility. This polymorphism causes a leu for pro-change at position 141 within uPA, and alters binding of the uPA zymogen to aggregated fibrin; 2) gain insight into the possible roles of leu-uPA versus pro-uPA by comparing individuals homozygous, for leu-uPA versus pro-uPA for relevant clinical and neuropathologic markers of AD, including uPA localization in AD brain; 3) evaluate the ability of leu- uPA versus pro-uPA to bind AB, activate plasminogen, and inhibit AB neurotoxicity in vitro; and 4) evaluate the role of uPA in AB clearance in vivo by quantifying AB accumulation in mice that are wild-type or genetically deficient for uPA. Overall, the focused approach proposed here will: 1) directly evaluate the possible role of uPA polymorphisms as a risk factor(s) for AD; and 2) provide insights into possible mechanisms underlying the differential uPA actions. These studies are significant, in that the identification of additional genetic risk factors for AD will aide in early AD diagnosis, and thereby facilitate drug discovery by identifying patients at high-risk for AD prior to symptomology. Moreover, by evaluating possible mechanisms underlying the enhanced susceptibility to AD, these studies may lead to the discovery of novel insights into the molecular mechanisms underlying AD, and thereby suggest new therapeutic approaches.