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(American Journal of Pathology. 2006;168:1986-1997.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051232

Genetically Augmenting Aß42 Levels in Skeletal Muscle Exacerbates Inclusion Body Myositis-Like Pathology and Motor Deficits in Transgenic Mice

Masashi Kitazawa, Kim N. Green, Antonella Caccamo and Frank M. LaFerla

From the Department of Neurobiology and Behavior, Laboratory of Molecular Neuropathogenesis, University of California, Irvine, Irvine, California

The pathogenic basis of inclusion body myositis (IBM), the leading muscle degenerative disease afflicting the elderly, is unknown, although the histopathological features are remarkably similar to those observed in Alzheimer’s disease. One leading hypothesis is that the buildup of amyloid-ß (Aß) peptide within selective skeletal muscle fibers contributes to the degenerative phenotype. Aß is a small peptide derived via endoproteolysis of the amyloid precursor protein (APP). To determine the pathogenic effect of augmenting Aß42 levels in skeletal muscle, we used a genetic approach to replace the endogenous wild-type presenilin-1 (PS1) allele with the PS1M146V allele in MCK-APP mice. Although APP transgene expression was unaltered, Aß levels, particularly Aß42, were elevated in skeletal muscle of the double transgenic (MCK-APP/PS1) mice compared to the parental MCK-APP line. Elevated phospho-tau accumulation was found in the MCK-APP/PS1 mice, and the greater activation of GSK-3ß and cdk5 were observed. Other IBM-like pathological features, such as inclusion bodies and inflammatory infiltrates, were more severe and prominent in the MCK-APP/PS1 mice. Motor coordination and balance were more adversely affected and manifested at an earlier age in the MCK-APP/PS1 mice. The data presented here provide experimental evidence that Aß42 plays a proximal and critical role in the muscle degenerative process.




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