AMYLOID DEPOSITION--AGING AND ALZHEIMERS DISEASE

某些神经病理损害是正常人大脑的特征 老年人和猴子，特别是阿尔茨海默氏症 患者，其中损害发生得更早，发生的范围更大 数字。相当大的少数(15%到50%之间) 阿尔茨海默病病例似乎是遗传的结果 常染色体显性突变的研究表明，单个基因 缺陷可导致神经病理改变。使用一种免疫化学/ 分子遗传学方法，编码一个组分的基因 正常人胞外蛋白沉积(称为“淀粉样蛋白”) 老年和阿尔茨海默病患者的大脑被克隆，并被发现编码 对于一种蛋白酶抑制剂，α1-抗凝乳杆菌胰蛋白酶。进一步 实验证实了这种蛋白酶的密切联系。 含有正常老年人蛋白质类淀粉样丝的抑制剂 和阿尔茨海默病的大脑。 未来五年的大部分时间将致力于确定如何 α1-抗糜蛋白酶对淀粉样蛋白沉积也有贡献 直接作为结构淀粉样组分，或间接作为 蛋白酶抑制剂。例如，阿尔法1- 抗糜蛋白酶在阿尔茨海默病脑中的过度表达表明 它可能会阻碍淀粉样蛋白沉积的正常清除。研究 将确定α1-抗凝乳杆菌胰蛋白酶的酶靶标 大脑中的抑制，表达阿尔法1的细胞- 抗凝乳糜酶和任何可能在阿尔法中出现的改变 1-抗凝乳糜酶基因、其表达或其编码蛋白， 在正常衰老或阿尔茨海默病期间。转基因小鼠将 其中α1-抗凝乳杆菌胰蛋白酶将在 一种受监管的方式来确定这种过度表达是否会导致 神经病理学，并提供用于测试的动物模型 阿尔茨海默病的潜在治疗方法和 “正常”的老年性神经病。

Certain neuropathological lesions characterize the brains of normal aged humans and monkeys, and particularly Alzheimer's disease patients, where the lesions occur much earlier and in far greater numbers. The substantial minority (between 15 and 50%) of Alzheimer cases which appear to be the result of the inheritance of an autosomal dominant mutation indicate that a single genetic defect can cause the neuropathology. Using an immunochemical/ molecular genetic approach, the gene coding for one component of the extracellular protein deposits (termed "amyloid") of normal aged and Alzheimer's disease brain was cloned, and found to code for a protease inhibitor, alpha 1-antichymotrypsin. Further experiments confirmed the intimate association of this protease inhibitor with the proteinaceous amyloid filaments of normal aged and Alzheimer's disease brain. Most of the next five years will be devoted to determining how alpha 1-antichymotrypsin contributes to amyloid deposition, either directly as a structural amyloid component, or indirectly as a protease inhibitor. For example, the fact that alpha 1- antichymotrypsin is overexpressed in Alzheimer brain suggests that it may prevent the normal clearing of amyloid deposits. Studies will determine the protease targets of alpha 1-antichymotrypsin inhibition in the brain, the cells expressing alpha 1- antichymotrypsin, and any alterations which may arise in the alpha 1-antichymotrypsin gene, its expression, or its encoded protein, during normal aging or Alzheimer's disease. Transgenic mice will be made in which alpha 1-antichymotrypsin will be overexpressed in a regulated manner to determine whether such over-expression leads to neuropathology, and to provide an animal model for testing potential therapeutic approaches to Alzheimer's disease and 'normal' senile neuropathy.