Transgenic mice over-expressing the C-99 fragment of βPP with an α-secretase site mutation develop a myopathy similar to human inclusion body myositis
Transgenic mice over-expressing the C-99 fragment of βPP with an α-secretase site mutation develop a myopathy similar to human inclusion body myositis
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DOI：
10.1016/s0002-9440(10)65681-7
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发表时间：
1998-12-01
影响因子：
6
通讯作者：
Martin, GM
中科院分区：
文献类型：
--
作者：
Jin, LW;Hearn, MG;Martin, GM
包涵体肌炎（IBM）是老年人最常见的肌肉疾病。淀粉样β蛋白（A β）已被证明在空泡化纤维中异常积累，并定位于IBM患者肌肉中的淀粉样原纤维。我们研究了一系列转基因小鼠的骨骼肌，这些小鼠过度表达β-淀粉样前体蛋白（β PP）的羧基末端99个氨基酸（C99），并将赖氨酸-612替换为缬氨酸（K612 V），旨在消除α-分泌酶识别并保留C99的A β结构域。大多数（87%）的24个月大的转基因小鼠表现出肌病的变化，其中约三分之一的变性纤维肌浆空泡和硫磺素-S阳性沉积。超微结构上，包涵体是短而细的淀粉样纤维聚集体，直径为6 - 8 nm。这些特征与人类IBM相似。使用抗A β抗体的免疫细胞化学显示转基因小鼠的大多数肌纤维中存在膜染色，以及萎缩纤维中的颗粒状或空泡状细胞质染色。蛋白质印迹显示，在具有最严重的IBM样病变的转基因小鼠的肌肉中，β PP的羧基末端片段的积累水平很高。这些转基因小鼠为研究IBM和阿尔茨海默病发病机制中关键因素的外周表达提供了模型。
Inclusion body myositis (IBM) is the most common muscle disease in the elderly. Amyloid-beta protein (A beta) has been shown to accumulate abnormally in the vacuolated fibers and to localize to amyloid-like fibrils in muscles from IBM patients. We studied the skeletal muscles from a line of transgenic mice over-expressing the carboxyl-terminal 99 amino acids (C99) of die P beta-amyloid precursor protein (beta PP) with a substitution of lysine-612 to valine (K612V), intended to abolish alpha-secretase recognition and to preserve the A beta domain of C99. The majority (87%) of the 24-month-old transgenic mice showed myopathic changes, and approximately one-third of them had degenerating fibers with sarcoplasmic vacuoles and thioflavin-S-positive deposits. Ultrastructurally, the inclusions were aggregates of short thin amyloid-like fibrils, 6 to 8 nn in diameter. These features are similar to those of human IBM. Immunocytochemistry using an antibody against A beta showed membranous staining in most muscle fibers of transgenic mice, as well as granular or vacuolar cytoplasmic staining in the atrophic fibers. Western blots showed a high level of accumulation of carboxyl-terminal fragments of beta PP in the muscles of the transgenic mice with the most severe IBM-like lesions. The expression of IBM-like lesions was age dependent, These transgenic mice provide a model for the study of IBM and for the peripheral expression of a key element in the pathogenesis of Alzheimer disease.