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(American Journal of Pathology. 1998;153:1679-1686.)
© 1998 American Society for Investigative Pathology

Short Communications

Transgenic Mice Over-Expressing the C-99 Fragment of ßPP with an -Secretase Site Mutation Develop a Myopathy Similar to Human Inclusion Body Myositis

Lee-Way Jin* , Mark G. Hearn* , Charles E. Ogburn* , Ngocthao Dang* , David Nochlin* , Warren C. Ladiges and George M. Martin*

From the Department of Pathology,* Laboratory of Neuropathology, and Department of Comparative Medicine, University of Washington, Seattle, Washington

Inclusion body myositis (IBM) is the most common muscle disease in the elderly. Amyloid-ß protein (Aß) 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 transgenic mice over-expressing the carboxyl-terminal 99 amino acids (C99) of the ß-amyloid precursor protein (ßPP) with a substitution of lysine-612 to valine (K612V), intended to abolish -secretase recognition and to preserve the Aß domain of C99. The majority (87%) of the 24-month-old transgenic mice showed myopathic changes, and approximately one-third of them had degenerating fibers with sarcoplasmic vacuoles and thioflavin-S-positive deposits. Ultrastructurally, the inclusions were aggregates of short thin amyloid-like fibrils, 6 to 8 nm in diameter. These features are similar to those of human IBM. Immunocytochemistry using an antibody against Aß showed membranous staining in most muscle fibers of transgenic mice, as well as granular or vacuolar cytoplasmic staining in the atrophic fibers. Western blots showed a high level of accumulation of carboxyl-terminal fragments of ßPP in the muscles of the transgenic mice with the most severe IBM-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 peripheral expression of a key element in the pathogenesis of Alzheimer disease.

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