ALZHEIMER BETA-AMYLOID PROTEIN IN DISEASED HUMAN MUSCLE

患病人体肌肉中的阿尔茨海默病 β-淀粉样蛋白

• 批准号: 2269793
• 负责人: VALERIE ASKANAS
• 金额: $ 6.88万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2269793
• 关键词: Alzheimer's disease; aging; amyloid proteins; animal tissue; biopsy; cytotoxicity; gene expression; histopathology; human subject; human tissue; immunoelectron microscopy; in situ hybridization; innervation; laboratory rat; mixed tissue /cell culture; muscle; muscle necrosis; myositis; neuromuscular junction; northern blottings; phenotype; synapses; transmission electron microscopy; western blottings

This proposal is based on our new findings that Alzheimer-like beta-amyloid protein betaAP is abnormally accumulated in vacuolated muscle fibers of patients with Sporadic (S) and Hereditary (H) Inclusion-Body Myositis (IBM). Heretofore, abnormalities in the brain involving betaAP accumulation were considered exclusive for Alzheimer's disease, Down syndrome, Dutch-type hereditary cerebrovascular amyloidosis and very advanced age. betaAP expression in normal and diseased human muscle has not been studied. The broad objective of our research is to utilize human muscle tissue-culture models for multidisciplinary molecular biology studies of the role of betaAP and its precursor protein (betaAPP). The long-term goals are to ascertain the role of betaAP in human muscle during: a) muscle necrosis; b) normal development, maturity and aging; c) development and maintenance of neuromuscular synapses. Specific Aims: 1. Establish whether betaAP will be abnormally accumulated in cultured muscle fibers of patients with a hereditary and sporadic IBM (in both betaAP is accumulated in the biopsied muscle). 2. Delineate whether development in culture of the morphologic phenotype characteristic of IBM correlates with an abnormal accumulation of betaAP and other betaAPP sequences. 3. Establish in cultured IBM muscle the sequence of developmental expression of the betaAPP gene, and accumulation of betaAP and possibly other betaAPP sequences. 4. Establish whether exogenously applied betaAP is toxic to cultured normal human muscle. This study is expected to establish whether: a) abnormal accumulation of betaAP in H-IBM is genetically determined; b) there is increased expression of the betaAPP gene in cultured H-IBM muscle; c) betaAP is toxic to human muscle and whether it produces the IBM phenotype. Because the pathologic accumulation of betaAP in IBM muscle and in AD brain have many similar features, their pathogeneses may share similar mechanisms. It is possible that the characteristic muscle degeneration occurring in IBM may represent a specific form of muscle aging, with similarities to brain aging in the Alzheimer phenotype. Accordingly, detailed molecular studies of pathogenic mechanisms in the more readily accessible biopsied living IBM muscle (as compared to brain), including use of cultured H-IBM muscle, might contribute to understanding AD.

这项建议是基于我们的新发现， β-淀粉样蛋白β AP在空泡细胞中异常积累， 散发性（S）和遗传性（H）患者的肌纤维 包涵体肌炎（IBM）。 因此，大脑异常 β-AP的积累被认为是阿尔茨海默氏症独有的 疾病，唐氏综合征，荷兰型遗传性脑血管淀粉样变性 而且年纪很大了β AP在正常人和患病人中的表达 肌肉尚未被研究。 我们研究的主要目标是利用人类肌肉 多学科分子生物学研究的组织培养模型 betaAP及其前体蛋白（betaAPP）的作用。 长期 目标是确定β AP在人类肌肉中的作用：a） 肌肉坏死; B）正常发育、成熟和衰老; c） 神经肌肉突触的发育和维持。 具体目标：1。确定β AP是否会异常蓄积 在遗传性和散发性IBM患者的培养肌纤维中， (in两种β AP都积聚在活组织检查的肌肉中）。2. 划定 无论是在培养物中形态表型的发育 IBM的特征与β AP的异常积累相关 和其他betaAPP序列。3.在培养的IBM肌肉中， β APP基因的发育表达序列，和 β AP和可能的其他β APP序列的积累。4.建立 外源性β AP对培养的正常人是否有毒性 肌肉. 这项研究预计将确定是否：a） H-IBM中的β AP是由遗传决定的; B） β APP基因在培养的H-IBM肌肉中的表达; c）β AP是 对人体肌肉有毒以及是否产生IBM表型。 因为β AP在IBM肌肉和AD中的病理性积累 脑有许多相似的特征，它们的发病机制可能有相似之处， 机制等 有可能是典型的肌肉退化 发生在IBM可能代表一种特定形式的肌肉老化， 与阿尔茨海默氏症表现型中的大脑衰老相似。 因此，委员会认为， 详细的致病机制的分子研究， 可访问的活体IBM肌肉（与大脑相比），包括 使用培养的H-IBM肌肉，可能有助于了解AD。