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我们理解和早期诊断该疾病至关重要。10号染色体区域包含至少一个晚发性阿尔茨海默病的易感基因座，并且与淀粉样蛋白B（ADI）血浆水平增加相关。编码尿激酶型纤溶酶原激活剂（uPA）的基因在此相关区域内。UPA在体外由AB处理的神经元诱导，在体内由AB负荷的Hsiao小鼠模型诱导。此外，uPA将纤溶酶原转化为活性蛋白酶纤溶酶，其以生理效率降解非聚集和聚集的AB。总之，ADi诱导uPA，这反过来又可以导致AB降解，表明AB聚集体清除的自我调节系统。综合考虑这些数据，我们假设10号染色体基因座包括调节uPA促进AD清除能力的uPA多态性。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多态性。在初步工作中，我们已经确定了两种uPA多态性，它们与AD易感性显著分离，并且处于强连锁不平衡中，包括（i）uPA内141位的pro被leu取代，这改变了uPA酶原与聚集的纤维蛋白的结合，以及（ii）已知对uPA诱导至关重要的AP-I位点3 '的两个碱基对的SNP。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学标志物的每种基因型纯合个体，深入了解有风险的uPA单倍型的可能作用，（iii）评估与AD风险相关的uPA多态性对uPA表达和功能的影响，和（iv）通过定量野生型或uPA遗传缺陷的小鼠中的AB积累来评价uPA在体内AB清除中的作用。 总体而言，本文提出的重点方法将（i）直接评估uPA多态性作为阿尔茨海默病风险因素的可能作用，以及（ii）提供对差异uPA作用的可能机制的见解。这些研究是重要的，因为阿尔茨海默氏病的其他遗传风险因素的鉴定将有助于早期AD诊断，从而通过在阿尔茨海默病学之前鉴定AD高风险患者来促进药物发现。此外，通过评估可能的机制增强阿尔茨海默病的易感性，这些研究可能会导致发现新的见解阿尔茨海默病的分子机制，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.