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ALZHEIMER-LIKE PATHOLOGY IN INCLUSION BODY MYOPATHY

包涵体肌病中的阿尔茨海默病样病理学

基本信息

批准号：
6884632
负责人：
VALERIE ASKANAS
金额：
$ 31.28万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-05-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6884632
关键词：
ALZHEIMER LIKE PATHOLOGY INCLUSION BODY

项目摘要

EXCEED THE SPACE PROVIDED. Sporadic inclusion-body myositis (s-IBM) is a progressive, highly debilitating, and the most common ¿nuscle 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: 3-amyloid precursor protein (¿APP) and of several other proteins accumulated in AD brain. Another similarity to AD is the presence of hereditary forms, termed "hereditary inclusion-body nyopathies (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 nuscle fibers of s- and h-IBM have evidence ofoxidative stress. Abnormalaccumulation of (3APP epitopes appears toprecede other abnormalities in s- and h-IBM muscle, in vivo and in vitro. Therefore, we propose that JAPP overexpressiom (whole molecule and/or A(3fragment) 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 >roposal 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 utilizing cultures of s-IBM muscle; and c) an induced model utilizing matured cultured normal human muscle fibers into which is transferred the (3APP gene; and 2) an induced in vivo aged-rat nodel based on transfer of the 3APP 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 ADgroup, 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 >atient 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. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。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）脑的那些显著相似的特征（“IBM-AD表型”），包括AD脑中积累的3-淀粉样前体蛋白（APP）和几种其他蛋白质的异常积累。与AD的另一个相似之处是存在称为“遗传性包涵体病（h-IBM）"的遗传形式，其在临床上比s-IBM更早地显现，但具有与s-IBM相同的肌肉纤维表型，尽管明显地比s-IBM稍晚。与AD脑类似，s-和h-IBM的异常神经纤维具有氧化应激的证据。在体内和体外，β APP表位的异常积累似乎可以减轻s-和h-IBM肌肉中的其他异常。因此，我们认为JAPP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A（3片段））引起分子紊乱，导致氧化应激，然后引起IBM特异性空泡肌纤维变性和IBM-AD表型的表达。这一研究解决了致病级联反应早期步骤的时间表，因此也解决了可能的机制。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，其中向所述肌纤维中转移了β APP基因;和2）基于将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，受累组织的体内老化可能是一个诱发因素，尤其是在偶发的、更常见的形式中。由于我们培养的自发和诱导的人体组织模型不能用于研究AD的脑参与，因此我们的结果可能为AD的发病机制和治疗提供重要的信息。性能现场=