This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Inclusion body myositis (IBM) is a common degenerative muscular disease afflicting a significant proportion of the elderly. It has no effective treatment. A hallmark of IBM pathology is an accumulation of amyloid precursor protein (APP) derived peptides, such as the 40 or 42 amino acid A? peptide or 83 or 99 residue C-terminal fragments (CTFs). IBM parallels AD with regards to the presence of A?, although in AD the peptide is deposited extracellularly instead of intracellularly, which is the case in IBM. In collaboration with Dr. Frank LaFerla at UC Irvine, we recently reported the development of a transgenic mouse model of IBM made by overexpressing APP in skeletal muscle via a creatine kinase promoter. To our knowledge, this is the only mouse model of IBM to utilize full length APP, and therefore offers a unique opportunity to study both the development of IBM pathology and to evaluate possible treatment strategies. Oneof the strengths of our group has been the development of potential AD therapeutics. We now propose to apply ourresources and knowledge to test three distinct approaches in the IBM mouse model, each targeting a specific aspect of APP processing: treatment with (i) typical and atypical NSAIDs (which reduce production of A?42), (ii) a potent global inhibitor of the ?-secretase enzyme (which reduces the production of all forms of A? and causes C-terminal fragments of APP to accumulate), or (iii) passive immunization with anti-A? antibodies (which target extracellular A?). These approaches are either currently available for patient use or are currently in clinical trial, and may thus be available within a few years as potential IBM therapies. In addition to answering important questions about potentially effective therapeutics, this study will also directly address several theoretical issues about the development of IBM pathology. IsA? production in general required for the development of the pathology, or is the longer, more amyloidogenic A?42 the critical factor (as it is in AD)? Alternatively, are the presence of intracellular APP CTFs responsible? Is the presence of secreted or extracellular A? important? A careful comparison of the outcomes of each aim will help to elucidate these issues, hopefully helping to resolve these long standing debates regarding IBM pathogenesis.
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