BETA-AMYLOID PRECURSOR EPITOPES IN MUSCLE-FIBERS OF INCLUSION-BODY MYOSITIS

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.