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: 6509651
• 负责人: VALERIE ASKANAS
• 金额: $ 33.84万
• 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/6509651
• 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.

散发性包络体肌炎（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，其肌纤维表型与阿尔茨海默病（AD）大脑（“IBM-AD表型”）的特征非常相似，包括β -淀粉样蛋白前体蛋白（betaAPP）和AD大脑中积累的其他几种蛋白质的异常积累。与阿尔茨海默病的另一个相似之处是存在遗传形式，称为“遗传性包涵体肌病（h-IBM）”，其临床表现早于s-IBM，但具有与s-IBM相同的肌肉纤维表型，尽管明显比s-IBM逊色。与AD大脑类似，s-和h-IBM的异常肌纤维有氧化应激的证据。在体内和体外实验中，β - app表位的异常积累似乎先于s-和h-IBM肌肉的其他异常。因此，我们提出betaAPP在老年（s-IBM）或遗传异常的成人（h-IBM）肌纤维环境中的过表达（整个分子和/或β片段）会引起分子紊乱，导致氧化应激，从而导致ibm特异性空泡肌纤维变性和IBM-AD表型的表达。本建议涉及致病级联早期步骤的时间表，因此可能的机制。它包括：1)三种长期培养模型，即a)利用h-IBM活检肌肉培养物的自发模型；b)利用s-IBM肌培养物的自发模型；c)利用成熟培养的正常人肌纤维诱导模型，将betaAPP基因转入该模型；2)将betaAPP基因转入老龄大鼠腓肠肌，在体内诱导建立老龄大鼠模型。将对异常培养物进行抗氧化治疗，包括雌激素治疗。我们假设，在IBM和AD组中，相关组织的体内老化可能是一个诱发因素，特别是在偶发的，更常见的形式中。由于我们培养的患者体内实际受影响的人体组织的自发和诱导模型无法用于研究阿尔茨海默病的大脑受累情况，因此我们的结果可能为阿尔茨海默病的发病机制和治疗提供重要的信息。