title: 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.
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.
authors.affiliation: Department of Pathology, University of Washington, Seattle 98195-6480, USA. lwjin@u.washington.edu
authors.forename: L W
authors.initials: LW
authors.lastname: Jin
authors.forename: M G
authors.initials: MG
authors.lastname: Hearn
authors.forename: C E
authors.initials: CE
authors.lastname: Ogburn
authors.forename: N
authors.initials: N
authors.lastname: Dang
authors.forename: D
authors.initials: D
authors.lastname: Nochlin
authors.forename: W C
authors.initials: WC
authors.lastname: Ladiges
authors.forename: G M
authors.initials: GM
authors.lastname: Martin
mesh_terms: D000367:Age Factors; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D010450:Endopeptidases / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009140:Musculoskeletal Diseases / Q000473:pathology*; D016296:Mutagenesis; D018979:Myositis, Inclusion Body / Q000473:pathology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse