Transgenic mice over-expressing the C-99 fragment of βPP with an α- 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, George M. Martin

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Abstract

Inclusion body myositis (IBM) is the most common muscle diseases in the elderly. Amyloid-β protein (Aβ) 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 β-amyloid precursor protein (βPP) with a substitution of lysine-612 to valine (K612V), intended to abolish α-secretase recognition and to preserve the Aβ domain of C99. The majority 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 Aβ 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 βPP 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.

Original languageEnglish (US)
Pages (from-to)1679-1686
Number of pages8
JournalAmerican Journal of Pathology
Volume153
Issue number6
StatePublished - Dec 1998
Externally publishedYes

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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