ALZHEIMER-LIKE PATHOLOGY IN INCLUSION BODY MYOPATHY

超出所提供的空间。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，它的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：3-淀粉样蛋白前体蛋白（¿APP）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，尽管明显不如s-IBM先进。与AD大脑类似，s-和h-IBM异常的肌肉纤维有氧化应激的证据。在体内和体外，（3APP）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））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>提案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肌肉培养的自发模型；c)利用培养成熟的正常人肌纤维，将3APP基因转入诱导模型；2)将3APP基因转入老龄大鼠腓肠肌，在体内诱导衰老大鼠模型。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，相关组织的体内老化可能是IBM和ad组的一个诱发因素，特别是在偶发的、更常见的形式中。由于我们在b>患者中实际受影响的人体组织培养的自发和诱导模型无法用于研究AD的大脑受损伤，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。网站性能 ======================================== 节结束 ===========================================

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===========================================