Askanas V, Alvarez R B, Engel W K
Department of Neurology University of Southern California School of Medicine, Los Angeles 90017-1912.
Ann Neurol. 1993 Oct;34(4):551-60. doi: 10.1002/ana.410340408.
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 (A beta), 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 A beta, two other epitopes, N-terminal and C-terminal, of the beta-amyloid precursor protein (beta PP) are abnormally accumulated in IBM vacuolated muscle fibers and similarly in hIBM. At the light microscopy level, immunoreactivities of N- and C-epitopes of beta PP closely colocalized with A beta and ubiquitin immunoreactivities. However, by immunogold electronmicroscopy, even though N-, C-, and A beta epitopes of beta PP and ubiquitin colocalized at the amorphous and dense floccular structures, only A beta was localized to the 6- to 10-nm amyloid-like fibrils and only ubiquitin was localized to CTFs. beta PP immunoreactive structures were often in proximity to CTFs, but CTFs themselves never contained beta PP immunoreactivities. The fact that A beta but not C- or N-terminal epitopes of beta PP localized to the 6- to 10-nm amyloid-like fibrils suggests that free A beta might be generated during beta PP processing and, after aggregation, may be responsible for the amyloid present within IBM muscle fibers. Our study demonstrates that three epitopes of beta PP 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.
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，其病理特征为含有15至21纳米胞质微管丝（CTF）的空泡化肌纤维。那些空泡化肌纤维还含有异常积聚的泛素和β-淀粉样蛋白（Aβ），并且如刚果红和结晶紫阳性所示，它们含有β折叠片中的淀粉样蛋白。使用几种特性明确的抗体，我们现已证明，除Aβ外，β-淀粉样前体蛋白（βPP）的另外两个表位，即N端和C端，在IBM空泡化肌纤维中异常积聚，在hIBM中情况类似。在光学显微镜水平，βPP的N端和C端表位的免疫反应性与Aβ和泛素免疫反应性紧密共定位。然而，通过免疫金电子显微镜观察，尽管βPP和泛素的N端、C端及Aβ表位在无定形和致密絮状结构中共定位，但只有Aβ定位于6至10纳米的淀粉样原纤维，只有泛素定位于CTF。βPP免疫反应性结构常靠近CTF，但CTF本身从不含有βPP免疫反应性。Aβ而非βPP的C端或N端表位定位于6至10纳米淀粉样原纤维这一事实表明，游离Aβ可能在βPP加工过程中产生，聚集后可能是IBM肌纤维内淀粉样蛋白的成因。我们的研究表明，βPP的三个表位在患病人类肌肉中异常积聚，因此这种现象并非阿尔茨海默病、唐氏综合征大脑和荷兰型脑血管淀粉样变性所特有。
