AMYLOID DEPOSITION--AGING AND ALZHEIMERS DISEASE

某些神经病理学病变是正常人大脑的特征， 老年人和猴子，特别是老年痴呆症 患者，病变发生得更早， 号码 绝大多数人（15%至50%） 老年痴呆症似乎是遗传的结果 常染色体显性突变表明， 缺陷会导致神经病变。 使用免疫化学/ 分子遗传学方法，基因编码的一个组成部分， 正常人的细胞外蛋白沉积物（称为“淀粉样蛋白”） 老年痴呆症患者的大脑被克隆， 蛋白酶抑制剂α 1-抗胰凝乳蛋白酶 进一步 实验证实了这种蛋白酶的密切关联 抑制剂与正常老年人的蛋白质淀粉样蛋白丝 和老年痴呆症的大脑。 未来五年的大部分时间将致力于确定如何 α 1-抗糜蛋白酶有助于淀粉样蛋白沉积， 直接作为淀粉样蛋白的结构成分，或间接作为 蛋白酶抑制剂 例如，α 1- 抗胰凝乳蛋白酶在阿尔茨海默氏症大脑中过度表达表明， 它可能会阻止淀粉样沉积物的正常清除。 研究 将确定α 1-抗胰凝乳蛋白酶的蛋白酶靶点 抑制在大脑中，细胞表达α 1- 抗胰凝乳蛋白酶，以及可能出现的α 1-抗胰凝乳蛋白酶基因、其表达或其编码的蛋白质， 在正常衰老或老年痴呆症期间。 转基因小鼠将 其中α 1-抗胰凝乳蛋白酶将在 确定这种过度表达是否导致 神经病理学，并提供一个动物模型， 阿尔茨海默病的潜在治疗方法， “正常”老年神经病。

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.