BETA-AMYLOID PRECURSOR EPITOPES IN MUSCLE-FIBERS OF INCLUSION-BODY MYOSITIS
BETA-AMYLOID PRECURSOR EPITOPES IN MUSCLE-FIBERS OF INCLUSION-BODY MYOSITIS
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DOI：
10.1002/ana.410340408
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发表时间：
1993-10-01
影响因子：
11.2
通讯作者：
ENGEL, WK
中科院分区：
文献类型：
--
作者：
ASKANAS, V;ALVAREZ, RB;ENGEL, WK
散发性包涵体肌炎（IBM）和遗传性包涵体肌病（hIBM）是严重的进行性肌肉疾病，病理特征为含有15- 21纳米细胞质管丝（CTFs）的液泡状肌纤维。这些空泡化的肌纤维也含有异常积累的泛素和β -淀粉样蛋白（Abeta），它们含有β -褶片中的淀粉样蛋白，如刚果红和结晶紫阳性所示。使用几种特征明确的抗体，我们现在已经证明，除了β， β -淀粉样蛋白前体蛋白（betaPP）的另外两个表位，n端和c端，在IBM液泡化肌纤维中异常积累，在hIBM中也是如此。在光镜下，betaPP的N-和c -表位的免疫反应性与β和泛素的免疫反应性密切共定位。然而，通过免疫金电镜，尽管betaPP和泛素的N-、C-和Abeta表位在无定形和致密的絮状结构上共定位，但只有Abeta定位在6- 10 nm的淀粉样原纤维上，只有泛素定位在CTFs上。BetaPP免疫反应性结构通常接近CTFs，但CTFs本身不含BetaPP免疫反应性。betaPP的β而不是C端或n端表位定位于6- 10 nm的淀粉样原纤维，这一事实表明，游离的β可能是在betaPP加工过程中产生的，并且在聚集后，可能是IBM肌纤维中淀粉样蛋白存在的原因。我们的研究表明，betaPP的三个表位在患病的人体肌肉中异常积累，因此这种现象并非阿尔茨海默病、唐氏综合征脑和荷兰型脑血管淀粉样变性所独有。
Sporadic inclusion body myositis (IBM) and hereditary inclusion body myopathy (hIBM) are severe and progressive muscle diseases, characterized pathologically by vacuolated muscle fibers that contain 15- to 21-nm cytoplasmic tubulofilaments (CTFs). Those vacuolated muscle fibers also contain abnormally accumulated ubiquitin and beta-amyloid protein (Abeta), and they contain amyloid in beta-pleated sheets as indicated by Congo red and crystal violet positivity. Using several well-characterized antibodies, we have now demonstrated that, in addition to Abeta, two other epitopes, N-terminal and C-terminal, of the beta-amyloid precursor protein (betaPP) are abnormally accumulated in IBM vacuolated muscle fibers and similarly in hIBM. At the light microscopy level, immunoreactivities of N- and C-epitopes of betaPP closely colocalized with Abeta and ubiquitin immunoreactivities. However, by immunogold electronmicroscopy, even though N-, C-, and Abeta epitopes of betaPP and ubiquitin colocalized at the amorphous and dense floccular structures, only Abeta was localized to the 6- to 10-nm amyloid-like fibrils and only ubiquitin was localized to CTFs. BetaPP immunoreactive structures were often in proximity to CTFs, but CTFs themselves never contained betaPP immunoreactivities. The fact that Abeta but not C- or N-terminal epitopes of betaPP localized to the 6- to 10-nm amyloid-like fibrils suggests that free Abeta might be generated during betaPP processing and, after aggregation, may be responsible for the amyloid present within IBM muscle fibers. Our study demonstrates that three epitopes of betaPP accumulate abnormally in diseased human muscle, and therefore this phenomenon is not unique to Alzheimer's disease, Down's syndrome brain, and Dutch-type cerebrovascular amyloidosis.