Urokinase-type plasminogen activator and Alzheimer's

描述(由申请人提供)：导致阿尔茨海默病(AD)易感性的遗传因素对于我们对疾病的理解和早期诊断至关重要。10号染色体区域至少包含一个晚发性阿尔茨海默病的易感基因，并与血浆淀粉样蛋白B(ADI)水平升高有关。编码尿激酶型纤溶酶原激活物(UPA)的基因就在这一牵连区域内。UPA是由AB处理的神经元在体外和体内AB负荷的小鼠模型中诱导的。此外，uPA还能将纤溶酶原转化为活性的纤溶酶，从而有效地降解非聚集和聚集的AB。综上所述，AdI诱导uPA，进而导致AB降解，提示AB聚集体的清除是一种自我调节系统。综合考虑这些数据，我们假设10号染色体基因座包括uPA多态(S)，该多态调节uPA对AD清除的贡献。为了评估这一假设，我们建议(I)确定与阿尔茨海默病分离的uPA基因多态。在前期工作中，我们已经鉴定了两个与AD易感性显著分离且处于强连锁不平衡的uPA多态，包括(I)uPA内141位的Leu取代Pro，它改变了uPA酶原与聚集纤维蛋白的结合；(Ii)一个SNP与AP-I位点的2个碱基对3‘，这是已知对uPA诱导至关重要的。我们还建议(Ii)通过比较阿尔茨海默病相关临床和神经病理标记物每个基因型的纯合个体来深入了解高危uPA单倍型的可能作用，(Iii)评估与AD风险相关的uPA多态对uPA表达和功能的影响，以及(Iv)通过量化uPA在野生型或遗传缺陷小鼠中的AB积累来评估uPA在体内AB清除中的作用。 总体而言，这里提出的重点方法将(I)直接评估uPA基因多态作为阿尔茨海默病危险因素(S)的可能作用，以及(Ii)为uPA不同作用的可能机制提供见解。这些研究具有重要意义，因为识别阿尔茨海默病的其他遗传风险因素将有助于AD的早期诊断，从而通过在症状出现之前识别AD的高风险患者来促进药物发现。此外，通过评估阿尔茨海默病易感性增加的可能机制，这些研究可能导致对阿尔茨海默病潜在分子机制的新见解，从而提出新的治疗方法。

DESCRIPTION (provided by applicant): Genetic factors that contribute to Alzheimer's disease (AD) susceptibility are critical to our understanding and early diagnosis of the disease. A chromosome 10 region contains at least one susceptibility locus for late onset Alzheimer's disease, and is associated with increased amyloid-B (ADi) plasma levels. The gene encoding urokinase-type plasminogen activator (uPA) is within this implicated region. UPA is induced by AB-treated neurons in vitro and in the Hsiao mouse model of AB burden in vivo. Moreover, uPA converts plasminogen to the active protease plasmin, which degrades both nonaggregated and aggregated AB with physiologic efficiency. In summation, ADi induces uPA, which can in turn lead to AB degradation, suggesting a self-regulated system for clearance of AB aggregates. Considering these data overall we hypothesize that the chromosome 10 loci includes a uPA polymorphism(s) that modulates uPA's ability to contribute to AD clearance. To evaluate this hypothesis, we propose to (i) identify uPA polymorphisms that segregate with Alzheimer's disease. In preliminary work we have identified two uPA polymorphisms that significantly segregate with AD susceptibility and are in strong linkage disequilibrium, including (i) a substitution of leu for pro at position 141 within uPA, which alters binding of the uPA zymogen to aggregated fibrin and (ii) a SNP two basepairs 3' to an AP-I site that is known to be critical for uPA induction. We also propose to (ii) Gain insight into the possible role of the at-risk uPA haplotype by comparing individuals homozygous for each genotype for relevant clinical and neuropathologic markers of Alzheimer's disease, (iii) Evaluate the effect of the uPA polymorphisms associated with AD risk on uPA expression and function, and (iv) Evaluate the role of uPA in AB clearance in vivo by quantifying AB accumulation in mice that are wildtype or genetically deficient for uPA. Overall, the focused approach proposed here will (i) directly evaluate the possible role of uPA polymorphisms as a risk factor(s) for Alzheimer's disease, and (ii) provide insights into possible mechanisms underlying differential uPA actions. These studies are significant in that the identification of additional genetic risk factors for Alzheimer's disease will aid 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 Alzheimer's disease, these studies may lead to the discovery of novel insights into the molecular mechanisms underlying Alzheimer's disease, and thereby suggest new therapeutic approaches.