ALZHEIMER BETA-AMYLOID PROTEIN IN DISEASED HUMAN MUSCLE

这项建议是基于我们的新发现，即类阿尔茨海默病 β-淀粉样蛋白β-AP在空泡状细胞中异常积聚 散发性(S)和遗传性(H)患者的肌纤维 包涵体肌炎(IBM)。到目前为止，大脑中的异常 涉及β-氨基丁酸积聚被认为是阿尔茨海默氏症的独有 疾病，唐氏综合征，荷兰型遗传性脑血管淀粉样变性 而且年纪也很大。β-AP在正常人和疾病人群中的表达 肌肉还没有被研究过。 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中的组织培养模型 BetaAP及其前体蛋白(BetaAPP)的作用。长期的 目标是确定BetaAP在人类肌肉中的作用：a) 肌肉坏死；b)正常发育、成熟和老化；c) 神经肌肉突触的发育和维持。 具体目标：1.确定BetaAP是否会异常积累 遗传性和散发性IBM患者的肌纤维培养 (在这两种情况下，β-AP都是在活检的肌肉中积累的)。2.划定 形态表型在培养中是否发育 IBM的特征与BetaAP的异常积累相关 和其他BetaAPP序列。3.在培养的IBM肌肉中建立 BetaAPP基因的发育表达序列，以及 积累BetaAP和可能的其他BetaAPP序列。4.建立 外源性应用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：a)异常堆积 H-IBM中的BetaAP是由基因决定的；b)有增加的 β-APP基因在培养的H-IBM肌肉中的表达 对人体肌肉有毒性，以及它是否产生IBM表型。 因为在IBM肌肉和AD中β-AP的病理性积聚 大脑有许多相似的特征，它们的发病机制可能相似 机械装置。有可能是典型的肌肉变性 发生在IBM中可能代表了一种特定形式的肌肉老化， 阿尔茨海默病表型与脑老化的相似性。因此， 对致病机制的详细分子研究更容易 可获取的活体IBM肌肉(与大脑相比)，包括 利用培养的H-IBM肌，可能有助于了解AD。

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.