STRUCTURE/FUNCTION ALZHEIMERS DISEASE PROTEASE INHIBITOR

美国65岁以上人口中约有5%患有 阿尔茨海默病（AD）。 尽管其流行，但没有有效的治疗方法 存在. 确诊是在尸检中使用组织病理学 这种疾病的一个标志是大脑中的淀粉样蛋白沉积， 脉管系统。 淀粉样蛋白沉积发生的频率是 比正常老化的大脑更大。 淀粉样蛋白来源于一种较大的 前体蛋白，其替代形式含有Kunitz蛋白酶 抑制剂. 因为淀粉样蛋白是通过蛋白水解裂解衍生的， 抑制剂结构域的功能可能在两个方面都具有关键作用， 正常和病理状态。 第一阶段的目的是重组 制备适用于三维结构的均相抑制剂， 分析. 第二阶段的目标是解决 抑制剂，鉴定其靶蛋白酶，并测定其 在淀粉样蛋白前体的蛋白水解加工中的功能作用。 结构和功能知识可以为治疗提供理论基础。 在AD中的干预

Approximately 5% of the over 65 population in the U.S. suffers from Alzheimer's disease (AD). Despite its prevalence no efficacious treatment exist. Definitive diagnosis is made on autopsy using the histopathological hallmark of the disease - amyloid deposition in the brain and cerebrovasculature. Amyloid deposition occurs at a frequency 1000-fold greater than in a normal aged brain. Amyloid is derived from a larger precursor protein, an alternative form of which harbors a Kunitz protease inhibitor. Because amyloid is derived via proteolytic cleavage, the function of the inhibitor domain may have a critical role in both the normal and pathological condition. The aim of phase I is to recombinantly produce homogeneous inhibitor suitable for three-dimensional structural analysis. Phase II will be aimed at resolving the tertiary structure of the inhibitor, identifying its target protease, and determining its functional role in the proteolytic processing of the amyloid precursor. Structural and functional knowledge may provide a rationale for therapeutic intervention in AD.