Inclusion body myositis-like phenotype induced by transgenic overexpression of beta APP in skeletal muscle.
Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease. Accumulation of the amyloid-beta peptide, which is derived from proteolysis of the larger amyloid-beta precursor protein (betaAPP), seems to be an early pathological event in Alzheimer's disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of betaAPP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted betaAPP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (>10 months) transgenic mice exhibit intracellular immunoreactivity to betaAPP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of betaAPP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for betaAPP mismetabolism in human IBM.
Sugarman
Michael C
MC
Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
Yamasaki
Tritia R
TR
Oddo
Salvatore
S
Echegoyen
Julio C
JC
Murphy
M Paul
MP
Golde
Todd E
TE
Jannatipour
Mehrdad
M
Leissring
Malcolm A
MA
LaFerla
Frank M
FM
D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D002467:Cell Nucleus / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D018482:Muscle, Skeletal / Q000378:metabolism*; D009220:Myositis / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D013997:Time Factors; D014018:Tissue Distribution; D019076:Transgenes
D016564:Amyloid beta-Protein Precursor; D018076:DNA, Complementary