Cystatin C colocalizes with amyloid‐β and coimmunoprecipitates with amyloid‐β precursor protein in sporadic inclusion‐body myositis muscles
Cystatin C colocalizes with amyloid‐β and coimmunoprecipitates with amyloid‐β precursor protein in sporadic inclusion‐body myositis muscles
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在散发性包涵体肌炎肌肉中，胱抑素 C 与淀粉样蛋白-β 共定位并与淀粉样蛋白-β 前体蛋白共免疫沉淀
DOI：
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发表时间：
2003
期刊：
影响因子：
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通讯作者：
V. Askanas
中科院分区：
文献类型：
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作者：
G. Vattemi;W. King Engel;J. Mcferrin;V. Askanas
半胱氨酸蛋白酶抑制剂C（CC）是一种内源性半胱氨酸蛋白酶抑制剂，在阿尔茨海默病（AD）大脑中的淀粉样蛋白-β（Aβ）淀粉样蛋白沉积物中积累，并被认为在AD发病机制中发挥作用。由于散发性包涵体肌炎（s-IBM）的化学形态学肌肉表型与AD脑表型有几个相似之处，包括Aβ沉积物的异常积累，我们研究了10例s-IBM肌肉活检组织和16例疾病和5例正常对照肌肉活检组织中CC的表达和定位。 在s-IBM肌肉活检和AβPP-过表达培养的人肌纤维中，通过联合免疫沉淀/免疫印迹技术研究了CC与淀粉样β前体蛋白（AβPP）的物理相互作用。在所有s-IBM肌肉活检中，CC免疫反应性与80-90%空泡化肌纤维中的Aβ免疫反应性包涵体共定位或相邻，主要位于其细胞质的非空泡化区域。超微结构上，CC免疫反应性与Aβ共定位于6-10 nm淀粉样纤维和絮状物上。 通过免疫印迹，与对照组相比，CC表达在IBM肌肉中强烈增加。通过免疫沉淀/免疫印迹实验，CC与AβPP在s-IBM肌肉和AβPP-过表达培养的正常人肌纤维中共免疫沉淀。我们的研究（i）首次证明CC与AβPP物理相关，（ii）表明CC可能在s‐IBM发病机制中发挥新作用，可能通过影响AβPP加工和Aβ沉积。
Cystatin C (CC), an endogenous cysteine protease inhibitor, is accumulated within amyloid‐β (Aβ) amyloid deposits in Alzheimer's disease (AD) brain and was proposed to play a role in the AD pathogenesis. Because the chemo‐morphologic muscle phenotype of sporadic inclusion‐body myositis (s‐IBM) has several similarities with the phenotype of AD brain, including abnormal accumulation of Aβ deposits, we studied expression and localization of CC in muscle biopsies of 10 s‐IBM, and 16 disease‐ and five normal‐control muscle biopsies. Physical interaction of CC with amyloid‐β precursor protein (AβPP) was studied by a combined immunoprecipitation/immunoblotting technique in the s‐IBM muscle biopsies and in AβPP‐overexpressing cultured human muscle fibers. In all s‐IBM muscle biopsies, CC‐immunoreactivity either colocalized with, or was adjacent to, the Aβ‐immunoreactive inclusions in 80–90% of the vacuolated muscle fibers, mostly in non‐vacuolated regions of their cytoplasm. Ultrastructurally, CC immunoreactivity‐colocalized with Aβ on 6–10 nm amyloid‐like fibrils and floccular material. By immunoblotting, CC expression was strongly increased in IBM muscle as compared to the controls. By immunoprecipitation/immunoblotting experiments, CC coimmunoprecipitated with AβPP, both in s‐IBM muscle and in AβPP‐overexpressing cultured normal human muscle fibers. Our studies (i) demonstrate for the first time that CC physically associates with AβPP, and (ii) suggest that CC may play a novel role in the s‐IBM pathogenesis, possibly by influencing AβPP processing and Aβ deposition.