Transgenic mice over-expressing the C-99 fragment of betaPP with an alpha-secretase site mutation develop a myopathy similar to human inclusion body myositis

Am J Pathol. 1998 Dec;153(6):1679-86. doi: 10.1016/s0002-9440(10)65681-7.

Abstract

Inclusion body myositis (IBM) is the most common muscle disease in the elderly. 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 transgenic mice over-expressing the carboxyl-terminal 99 amino acids (C99) of the beta-amyloid precursor protein (betaPP) 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 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 A beta 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 betaPP 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age Factors
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases
  • Blotting, Western
  • Brain / pathology
  • Endopeptidases / metabolism*
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / ultrastructure
  • Musculoskeletal Diseases / pathology*
  • Mutagenesis
  • Myositis, Inclusion Body / pathology*

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse