ALZHEIMER-LIKE PATHOLOGY IN INCLUSION BODY MYOPATHY

包涵体肌病中的阿尔茨海默病样病理学

• 批准号: 2837339
• 负责人: VALERIE ASKANAS
• 金额: $ 23.04万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2837339
• 关键词: Alzheimer's disease; aging; amyloid proteins; animal old age; antioxidants; biomarker; cellular pathology; disease /disorder model; human tissue; immunocytochemistry; in situ hybridization; inclusion body; laboratory rat; myositis; northern blottings; oxidative stress; pathologic process; striated muscles; tissue /cell culture; transfection; western blottings

Sporadic inclusion-body myositis (s-IBM) is a progressive, highly debilitating, and the most common muscle disease of older persons (over age 60). An intriguing aspect of s-IBM is that its muscle fiber phenotype has features remarkably similar to those of Alzheimer Disease (AD) brain ("IBM-AD phenotype"), including abnormal accumulations of: beta-amyloid precursor protein (betaAPP) and of several other proteins accumulated in AD brain. Another similarity to AD is the presence of hereditary forms, termed "hereditary inclusion-body myopathies (h-IBM)", which clinically are manifest earlier than s-IBM, but have a muscle- fiber phenotype identical to, though apparently somewhat less advanced than, that of s-IBM. Similarly to AD brain, abnormal muscle fibers of s- and h-IBM have evidence of oxidative stress. Abnormal accumulation of betaAPP epitopes appears to precede other abnormalities in s- and h-IBM muscle, in vivo and in vitro. Therefore, we propose that betaAPP overexpression (whole molecule and/or Abeta fragment) in the milieu of aged (s-IBM) or genetically-abnormal adult (h-IBM)muscle fibers causes molecular disturbances leading to oxidative stress, which then causes the IBM-specific vacuolar muscle-fiber degeneration and expression of the IBM-AD phenotype. This proposal addresses the schedule, and therefore possible mechanisms, of early steps in the pathogenic cascade. It involves: 1) three long-term culture models, namely, a) a spontaneous model utilizing cultures of biopsied muscle of h-IBM; b) a spontaneous model of utilizing cultures of s-IBM muscle; and c) an induced model utilizing matured cultured normal human muscle fibers into which is transferred the betaAPP gene; and 2) an induced in vivo aged-rat model based on transfer of the betaAPP gene into aged-rat gastrocnemius muscle. Anti-oxidant treatments, including estrogens, will be done on abnormal cultures. We postulate that in vivo aging of the involved tissues may be a predisposing factor(s) in both the IBM's and the AD group, especially in the sporadic, more common, forms of each. Because our type of cultured spontaneous and induced models of the human tissue actually affected in the patient are not available to study brain involvement in the AD's, possibly our results may provide important information relevant to the pathogenesis and treatment of the AD's.

散发性包涵体肌炎（s-IBM）是一种进行性、高度衰弱的老年人（60岁以上）最常见的肌肉疾病。 s-IBM的一个有趣的方面是，其肌纤维表型具有与阿尔茨海默病（AD）脑的特征（“IBM-AD表型”）显著相似的特征，包括β-淀粉样前体蛋白（β APP）和AD脑中积累的几种其他蛋白质的异常积累。与AD的另一个相似性是存在称为“遗传性包涵体肌病（h-IBM）"的遗传形式，其在临床上比s-IBM更早显现，但具有与s-IBM相同的肌纤维表型，尽管明显地比s-IBM稍晚。 类似于AD脑，s-和h-IBM的异常肌纤维有氧化应激的证据。在体内和体外，β APP表位的异常积累似乎先于s-和h-IBM肌肉中的其他异常。因此，我们提出，β APP过度表达（整个分子和/或Abeta片段）的环境中的老年人（s-IBM）或遗传异常的成人（h-IBM）肌肉纤维引起分子干扰，导致氧化应激，然后导致IBM特异性空泡肌纤维变性和表达的IBM-AD表型。 该提案涉及致病级联早期步骤的时间表，因此也涉及可能的机制。 它包括：1）三种长期培养模型，即，a）利用h-IBM活组织检查肌肉培养物的自发模型; B）利用s-IBM肌肉培养物的自发模型;和c）利用成熟培养的正常人肌纤维的诱导模型，其中β APP基因被转移到所述肌纤维中;和2）基于β APP基因转移到老年大鼠腓肠肌中的体内诱导老年大鼠模型。 将对异常培养物进行抗氧化治疗，包括雌激素。 我们推测，在IBM和AD组中，尤其是在偶发的、更常见的形式中，所涉及的组织的体内老化可能是一个诱发因素。因为我们的培养的自发和诱导的模型的人组织，实际上影响了病人是不可用的研究大脑参与AD的，可能我们的结果可能会提供重要的信息相关的发病机制和治疗的AD的。