AGING AND SENILE DEMENTIA OF THE ALZHEIMER TYPE

阿尔茨海默病是一种病因不明但神经病理的疾病 对受影响个体的脑组织检查显示出特征 称为神经炎(老年性)斑块和神经纤维缠结的结构。 指导所述实验建议的工作假设 这就是对生化异常的清楚理解 促进这些结构的形成将使我们更接近 了解阿尔茨海默病的分子基础。因此，a 提出了一系列的研究建议。在分子生物学方面的工作 淀粉样前体蛋白(APP)将解决 培养的细胞，包括小胶质细胞，产生APP的不足和过度。 APP的加工，包括可能产生和挤出Beta- 蛋白质，将被研究。APP的分布和假定截断 表格将通过免疫组织化学进行检查。β-半乳糖胺的细胞毒性 大脑中的蛋白质可能具有膜功能。各种不同类型的抗体 该应用程序的部分功能将用于搜索阿尔茨海默病的特定表位 受影响个体的脑脊液。成对的螺旋细丝将是 经过审查，预计对组成成分的理解 将对导致它们组装的机制有深入的了解 进入这些病理结构。蛋白酶是任何 关于缠结和斑块的讨论，因为如果它们的蛋白质成分 如果在原位消化，这些结构大概不会形成。因此，工作 关于最近发现的一种名为高分子量的脑蛋白酶 蛋白水解酶，包括在这项建议中。除了淀粉样蛋白和缠结，其他 葡萄糖代谢中的生化异常，这将在 程序。 预计综合来自这些不同方面的结果 方法将增进我们对分子病理学的理解。 阿尔茨海默病的起源，因此将有助于 为受害者提供合理的治疗。

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.