AGING AND SENILE DEMENTIA OF THE ALZHEIMER TYPE

阿尔茨海默病是一种病因不明的疾病，但神经病理学 检查受影响个体的脑组织显示出特征性的 结构称为神经炎（老年）斑和神经纤维缠结。 指导实验建议的工作假设概述 这是一个清楚的了解生化异常， 促进这些结构的形成将使我们更接近一个 了解阿尔茨海默病的分子基础。 因此 提出了一系列的研究。 在分子生物学方面的工作 淀粉样前体蛋白（APP）将解决细胞的后果， 培养细胞（包括小胶质细胞）APP的生产不足和过度。 APP的加工，包括可能产生和挤出β- 蛋白质将被研究。 APP的分布和假定的截短 将通过免疫组织化学检查形式。 β- 脑中的蛋白质可包括膜功能。 抗体对各种 APP的一部分将用于搜索阿尔茨海默氏症特异性表位， 受影响个体的CSF。 成对的螺旋状细丝将 检查，并预计，了解成分 的PHF将深入了解导致其组装的机制 这些病理结构。 蛋白酶是任何 讨论缠结和斑块，因为如果它们的蛋白质成分 被就地消化，这些结构大概不会形成。 因此，工作 最近发现的一种大脑蛋白酶，称为高分子量 蛋白酶，包括在该提案中。 除了淀粉样蛋白和缠结，其他 葡萄糖代谢的生化畸变，这将在 程序. 预计这些不同的结果的整合 方法将增强我们对分子病理学的理解， 老年痴呆症的起源，从而有助于发展 对受害者进行理性治疗

Alzheimer Disease is a malady of unknown etiology, but neuropathological examination of brain tissues of affected individuals reveals characteristic structures known as neuritic (senile) plaques and neurofibrillary tangles. The working hypothesis that guides proposal of the experiments outlined here is that a clear understanding of the biochemical abnormalities that foster the formation of these structures will lead us closer to an understanding of the molecular basis of Alzheimer Disease. Therefore, a series of studies is proposed. Work on the molecular biology of the amyloid precursor protein (APP) will address the cellular consequences of under- and over-production of APP by cultured cells, including microglia. Processing of APP, including possible generation and extrusion of beta- protein, will be studied. The distribution of APP and putative truncated forms will be examined by immunohistochemistry. The cytotoxicity of beta- protein in the brain may comprise membrane function. Antibodies to various parts of the APP will be used to search for Alzheimer specific epitopes in CSF of affected individuals. The paired helical filaments will be examined, and it is anticipated that an understanding of the constituents of PHF will give insights into the mechanisms that lead to their assembly into these pathological structures. Proteases are fundamental to any discussion of tangles and plaques, because if their protein constituents were digested in situ the structures presumably would not form. Thus, work on a recently discovered brain protease, called high molecular weight protease, is included in this proposal. Besides amyloid and tangles, other biochemical aberrations in glucose metabolism, which will be studied in the Program. It is anticipated that integration of the results from these diverse approaches will enhance our understanding of the molecular pathological origins of Alzheimer Disease, and will thus contribute to development of rational therapy for its victims.