The investigator proposes to develop and characterize novel transgenic mouse models to study the molecular pathogenesis of inclusion body myositis (IBM). Although the primary cause of this disease remains unknown, surprisingly many of the pathobiological features that occur in IBM are known to be long-standing alterations that occur in the brains of those afflicted with Alzheimer's disease (AD). Histochemical and immunological reagents have conclusively demonstrated that Abeta deposits accumulate in muscle fibers in IBM. Notably, Abeta accumulation does not occur in other muscle disorders. These findings are significant and point to Abeta and its precursor molecule, beta-amyloid precursor protein (betaAPP), as playing a critical role in the pathogenesis of this common, age-related myopathy. By targeting betaAPP and Abeta over expression to muscle, the potential effects of these molecules in the pathogenesis of IBM can be evaluated. The investigator has derived transgenic mice in which the muscle creatine kinase (MCK) promoter drives betaAPP expression in skeletal muscle. Transgenic over expression of betaAPP in skeletal muscle induces an IBM-like phenotype, including intracellular Abeta deposits, centric nuclei, cellular inflammation, and an age-related deficit in motor function.
The Aims of this application focus on determining factors that can modulate the IBM phenotype in these transgenic mice.
In Aim 1, the MCK-betaAPPtransgenic mice will be crossed to mutant presenilin-l knock-in mice. Since mutations in presenilins augment Abeta formation in every tissue that has been analyzed, these double transgenic mice are expected to develop muscle pathology at an earlier age or exhibit an exacerbated pathology.
In Aim 2, attempts will be made to attenuate the IBM-like pathology either through the use of an Abeta vaccine or through the use of pharmacological inhibitors (gamma-secretase inhibitors) that can prevent Abeta production.
Aim 3 will focus on characterizing a novel transgenic mouse model that over expresses only the Abeta peptide; this will indicate if Abeta is sufficient to act as the molecular trigger that induces IBM or whether another derivative product of betaAPP is the trigger.
