BACE1 and BACE2 in pathologic and normal human muscle
BACE1 and BACE2 in pathologic and normal human muscle
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DOI：
10.1016/s0014-4886(02)00025-0
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发表时间：
2003-02-01
影响因子：
5.3
通讯作者：
Askanas, V
中科院分区：
文献类型：
--
作者：
Vattemi, G;Engel, WK;Askanas, V
BACE 1和BACE 2是最近发现的参与淀粉样蛋白P前体蛋白（APPP）加工的酶。他们的发现对于理解淀粉样蛋白β生成的机制以及阿尔茨海默病（AD）的发病机制有重要贡献。散发性包涵体肌炎（s-IBM）和遗传性包涵体肌病（h-IBM）是进行性肌肉疾病，其中APPP的过度产生及其可能有毒的蛋白水解产物淀粉样蛋白-β（Abeta）在异常肌纤维中的积累似乎在致病级联中起重要的上游作用。在正常人肌肉中，APPP也被证明存在，并可能在（a）神经肌肉接头和（B）肌肉发育过程中发挥作用。为了研究BACE I和BACE 2是否在正常和患病的人类肌肉中发挥作用，我们现在已经通过免疫细胞化学和免疫印迹在35个人类肌肉活检组织中研究了它们，包括：5个s-IBM; 5个染色体9 p1连锁的四头体保留的h-IBM;和25个对照肌肉活检组织。此外，研究了BACE 1和BACE 2在正常培养的人肌肉中的表达。我们的研究表明，BACE 1和BACE 2（a）在正常成人肌肉的神经肌肉接头的突触后结构域中表达，并且在培养的人肌肉中表达：（B）在s-IBM和h-IBM空泡化肌纤维中以斑块样包涵体的形式积累，并且（c）在坏死肌纤维中具有免疫反应性。因此，BACE 1和BACE 2参与人体肌肉的正常和异常过程，这表明它们的功能比以前认为的更广泛。(C)2003 Elsevier Science（美国）。All rights reserved.
BACE1 and BACE2 are recently discovered enzymes participating in processing of amyloid P precursor protein (APPP). Their discovery is contributing importantly to understanding the mechanism of amyloid-beta generation, and hence the pathogenesis of Alzheimer's disease (AD). Sporadic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopathy (h-IBM) are progressive muscle diseases in which overproduction of APPP and accumulation of its presumably toxic proteolytic product amyloid-beta (Abeta) in abnormal muscle fibers appear to play an important upstream role in the pathogenic cascade. In normal human muscle APPP was also shown to be present and presumably playing a role (a) at neuromuscular junctions and (b) during muscle development. To investigate whether BACE I and BACE2 play a role in normal and diseased human muscle, we have now studied them by immunocytochemistry and immunoblotting in 35 human muscle biopsies, including: 5 s-IBM; 5 chromosome-9p1-linked quadriceps-sparing h-IBM; and 25 control muscle biopsies. In addition, expression of BACE1 and BACE2 was studied in normal cultured human muscle. Our studies demonstrate that BACE1 and BACE2 (a) are expressed in normal adult muscle at the postsynaptic domain of neuromuscular junctions, and in cultured human muscle: (b) are accumulated in the form of plaque-like inclusions in both s-IBM and h-IBM vacuolated muscle fibers-, and (c) are immunoreactive in necrotizing muscle fibers. Accordingly, BACE1 and BACE2 participate in normal and abnormal processes of human muscle, suggesting that their functions are broader than previously thought. (C) 2003 Elsevier Science (USA). All rights reserved.