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

Sporadic inclusion body myositis (IBM) and hereditary inclusion body m yopathy (hIBM) are severe and progressive muscle diseases, characteriz ed pathologically by vacuolated muscle fibers that contain 15- to 21-n m cytoplasmic tubulofilaments (CTFs). Those vacuolated muscle fibers a lso 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-charact erized antibodies, we have now demonstrated that, in addition to Abeta , two other epitopes, N-terminal and C-terminal, of the beta-amyloid p recursor protein (betaPP) are abnormally accumulated in IBM vacuolated muscle fibers and similarly in hIBM. At the light microscopy level, i mmunoreactivities of N- and C-epitopes of betaPP closely colocalized w ith Abeta and ubiquitin immunoreactivities. However, by immunogold ele ctronmicroscopy, 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-termina l 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 wit hin IBM muscle fibers. Our study demonstrates that three epitopes of b etaPP accumulate abnormally in diseased human muscle, and therefore th is phenomenon is not unique to Alzheimer's disease, Down's syndrome br ain, and Dutch-type cerebrovascular amyloidosis.