Sugarman Michael C, Yamasaki Tritia R, Oddo Salvatore, Echegoyen Julio C, Murphy M Paul, Golde Todd E, Jannatipour Mehrdad, Leissring Malcolm A, LaFerla Frank M
Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6334-9. doi: 10.1073/pnas.082545599. Epub 2002 Apr 23.
Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease. Accumulation of the amyloid-beta peptide, which is derived from proteolysis of the larger amyloid-beta precursor protein (betaAPP), seems to be an early pathological event in Alzheimer's disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of betaAPP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted betaAPP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (>10 months) transgenic mice exhibit intracellular immunoreactivity to betaAPP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of betaAPP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for betaAPP mismetabolism in human IBM.
包涵体肌炎（IBM）是老年人群中最常见的与年龄相关的肌肉疾病，是一种无法治愈的疾病，会导致严重残疾。散发性IBM的病因不明，尽管受影响的肌纤维具有许多传统上与神经退行性脑疾病（如阿尔茨海默病）相关的病理生化改变。淀粉样β肽由较大的淀粉样β前体蛋白（βAPP）蛋白水解产生，其积累似乎是阿尔茨海默病以及IBM的早期病理事件，在IBM中，它主要在受影响的肌纤维内细胞内发生。为了阐明βAPP代谢异常在IBM发病机制中的可能作用，我们构建了转基因小鼠，通过使用肌肉肌酸激酶启动子将βAPP的过表达选择性地靶向骨骼肌。在此我们报告，年龄较大（>10个月）的转基因小鼠骨骼肌中出现对βAPP及其蛋白水解衍生物的细胞内免疫反应性。在这个转基因模型中，βAPP的选择性过表达导致了IBM特有的其他组织病理学和临床特征的出现，包括中心核、炎症和运动功能缺陷。这些结果与βAPP代谢异常在人类IBM发病机制中的致病作用一致。
