UPA Polymorphisms as a Differential Risk Factor for AD

描述(由申请人提供)：确定遗传风险因素 与阿尔茨海默病(AD)相关的疾病对防治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为 至少包含一个晚发性AD易感基因(1-3)，其中一个 研究小组还发现，这一区域与血浆中 β-淀粉样蛋白(AB)(1)。编码尿激酶型纤溶酶原激活物的基因 (UPA)这一牵连区域内的地图。此前，我们报道了uPA是 AB处理的神经细胞在体外和AB小鼠模型中的诱导 体内负担(4)。此外，uPA将纤溶酶原转化为活性蛋白酶。 纤溶酶，对非聚集AB和聚集AB均有生理降解作用 效率(初步结果和[4，5])。AB积累是一个标志 AD，并可能是这种疾病的病因。从整体上考虑这些数据，我们 假设10号染色体上的一个基因座是uPA多态 调节uPA的贡献能力，促进AB清除。来评估这一点 假设，我们建议：1)评估uPA基因在AD中的多态频率 并与对照患者辨别多态性(S)，与AD分离。在……里面 初步工作，我们发现了一种uPA多态，它显著地 与阿尔茨海默病易感性隔离。这种多态会导致亮氨酸 促进uPA内第141位的改变，并改变uPA酶原与 聚集的纤维蛋白；2)了解Leu-uPA与 通过比较纯合子的个体，亮氨酸-uPA与前uPA 阿尔茨海默病的相关临床和神经病理标志，包括uPA定位 3)比较Leu-uPA与Pro-uPA结合AB的能力， 激活纤溶酶原，体外抑制AB神经毒性；4)评价 尿激酶型纤溶酶原激活剂在体内AB清除中的作用 是野生型的或uPA基因缺陷的。总体而言，专注于 这里提出的方法将：1)直接评估upa可能发挥的作用 基因多态是AD的危险因素(S)；以及2)提供了对可能的 UPA不同行动背后的机制。这些研究是 重要的是，识别额外的遗传风险因素 AD将有助于AD的早期诊断，从而通过以下方式促进药物发现 在出现症状之前确定AD的高危患者。此外，通过 评估阿尔茨海默病易感性增强的可能机制， 这些研究可能会导致对分子的新见解的发现 阿尔茨海默病的潜在机制，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.