ALZHEIMER-LIKE PATHOLOGY IN INCLUSION BODY MYOPATHY

散发性包涵体肌炎(S-IBM)是一种进行性、高度衰弱的肌肉疾病，是老年人(60岁以上)最常见的肌肉疾病。S-IBM耐人寻味的一点是，它的肌肉纤维表型与阿尔茨海默病(AD)脑的特征非常相似(“IBM-AD表型”)，包括AD大脑中异常积累的：β-淀粉样前体蛋白(β-APP)和其他几种蛋白质。与AD的另一个相似之处是存在遗传性形式，称为遗传性包涵体肌病(h-IBM)，临床上早于S-IBM表现，但肌纤维表型与S-IBM相同，但明显不如S-IBM先进。与AD脑类似，S和h-IBM的异常肌纤维也有氧化应激的证据。在体内和体外，在S和h-IBM肌肉中，βAPP表位的异常积累似乎先于其他异常。因此，我们认为，在老年(S-IBM)或遗传异常成人(h-IBM)肌纤维环境中，βAPP的过度表达(全分子和/或Aβ片段)会引起分子紊乱，导致氧化应激，进而导致IBM特有的空泡肌纤维变性和IBM-AD表型的表达。这项建议涉及致病级联早期步骤的时间表，因此也涉及可能的机制。包括：1)三种长期培养模型，即a)利用h-IBM肌组织培养的自发模型；b)利用S-ibm肌肉培养的自发模型；c)利用成熟培养的人正常肌肉纤维导入βAPP基因的诱导模型；2)基于βAPP基因转入老龄大鼠腓肠肌的体内诱导衰老模型。包括雌激素在内的抗氧化治疗将在异常培养物上进行。我们推测，受累组织的体内老化可能是IBM和AD组的一个易感因素(S)，特别是在散发性的、更常见的各自的形式中。由于我们所建立的在患者体内实际受影响的人体组织的自发和诱导培养模型不能用于研究AD的脑参与，我们的结果可能为AD的发病机制和治疗提供重要的信息。

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.