β‐Amyloid precursor epitopes in muscle fibers of inclusion body myositis

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Abstract
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 β-amyloid protein (Aβ), and they contain amyloid in β-pleated sheets as indicated by Congo red and crystal violet positivity. Using several well-characterized antibodies, we have now demonstrated that, in addition to Aβ, two other epitopes, N-terminal and C-terminal, of the β-amyloid precursor protein (βPP) are abnormally accumulated in IBM vacuolated muscle fibers and similarly in hIBM. At the light microscopy level, immunoreactivities of N- and C-epitopes of βPP closely colocalized with Aβ and ubiquitin immunoreactivities. However, by immunogold electronmicroscopy, even though N-, C-, and Aβ epitopes of βPP and ubiquitin colocalized at the amorphous and dense floccular structures, only Aβ was localized to the 6- to 10-nm amyloid-like fibrils and only ubiquitin was localized to CTFs. βPP immunoreactive structures were often in proximity to CTFs, but CTFs themselves never contained βPP immunoreactivities. The fact that Aβ but not C- or N-terminal epitopes of βPP localized to the 6- to 10-nm amyloid-like fibrils suggests that free Aβ might be generated during βPP processing and, after aggregation, may be responsible for the amyloid present within IBM muscle fibers. Our study demonstrates that three epitopes of βPP 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.
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