Transgenic mice over-expressing the C-99 fragment of beta PP with an alpha-secretase site mutation develop a myopathy similar to human inclusion bodymyositis

Inclusion body myositis (IBM) is the most common muscle disease in the elde rly. Amyloid-beta protein (A beta) has been shown to accumulate abnormally in the vacuolated fibers and to localize to amyloid-like fibrils in muscles from IBM patients. We studied the skeletal muscles from a line of transgen ic mice over-expressing the carboxyl-terminal 99 amino acids (C99) of die P beta-amyloid precursor protein (beta PP) with a substitution of lysine-612 to valine (K612V), intended to abolish alpha-secretase recognition and to preserve the A beta domain of C99. The majority (87%) of the 24-month-old t ransgenic mice showed myopathic changes, and approximately one-third of the m had degenerating fibers with sarcoplasmic vacuoles and thioflavin-S-posit ive deposits. Ultrastructurally, the inclusions were aggregates of short th in amyloid-like fibrils, 6 to 8 nn in diameter. These features are similar to those of human IBM. Immunocytochemistry using an antibody against A beta showed membranous staining in most muscle fibers of transgenic mice, as we ll as granular or vacuolar cytoplasmic staining in the atrophic fibers. Wes tern blots showed a high level of accumulation of carboxyl-terminal fragmen ts of beta PP in the muscles of the transgenic mice with the most severe IB M-like lesions. The expression of IBM-like lesions was age dependent, These transgenic mice provide a model for the study of IBM and for the periphera l expression of a key element in the pathogenesis of Alzheimer disease.