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: 6098054
• 负责人: VALERIE ASKANAS
• 金额: $ 33.2万
• 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: 1999-07-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098054
• 关键词: Alzheimer's disease; aging; amyloid proteins; animal old age; biopsy; disease /disorder model; gastrocnemius muscle; gene expression; histopathology; human tissue; immunocytochemistry; inclusion body; laboratory rat; myofibrils; myositis; northern blottings; oxidative stress; phenotype; tissue /cell culture; 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 muscle, in vivo and in vitro. Therefore, we propose that betaAPP over-expression (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 the IBM-specific vacuolar muscle-fiber degeneration and expression of the IBM-AD phenotype. This proposal addresses the schedule, and therefore the possible mechanisms, of the early steps in the pathogenic cascade. It involves: 1) three long-term in vitro models, namely, a) spontaneous model utilizing cultures of s-IBM muscle; and cc) 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 involve tissues may be a predisposing factor(s) in both the AD group and the IBM's, 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 otherwise- unavailable 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 老年人最常见的肌肉疾病（超过 60岁）。s-IBM的一个有趣的方面是它的肌肉纤维 表型与阿尔茨海默病的特征非常相似 (AD)脑（“IBM-AD表型”），包括以下物质的异常积累： β-淀粉样前体蛋白（betaAPP）和其他几种蛋白质 在AD脑中积累。与AD的另一个相似之处是 遗传形式，称为“遗传性包涵体肌病（h-IBM）"， 在临床上比s-IBM更早出现，但有肌肉- 纤维表型与相同，但明显不太先进 而不是IBM。与AD大脑类似， s-和h-IBM肌肉，在体内和体外。因此，我们建议， β APP过表达（在细胞中的整个分子和/或Abeta片段） 老化（s-IBM）或遗传异常成人（h-IBM）肌肉环境 纤维引起分子干扰，导致IBM特异性 空泡性肌纤维变性与IBM-AD的表达 表型本提案涉及时间表，因此， 可能的机制，在致病级联的早期步骤。它 涉及：1）三种长期体外模型，即a）自发 利用s-IBM肌肉培养物的模型;和cc）诱导模型 利用成熟培养的正常人肌肉纤维， 转β APP基因;和2）诱导的体内衰老大鼠模型 基于将betaAPP基因转移到老年大鼠腓肠肌中， 肌肉.抗氧化治疗，包括雌激素，将在 异常文化我们假设，在体内老化的涉及 组织可能是AD组和非AD组中的一个诱发因素。 IBM的，特别是在零星的，更常见的，每一种形式。因为 我们培养的自发和诱导的人体组织模型 实际上受影响的患者无法用于研究大脑 参与广告，可能我们的结果可能会提供其他- 与发病机制和治疗相关的信息不可用 AD的。