Molecular interactions of inflammation and beta-amyloid-associated degeneration in muscle as pathomechanisms of Inclusion Body Myositis

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Sporadic Inclusion Body Myositis (sIBM) is a severely disabling myopathy for that no effective treatment is available. Cleaved from amyloid-precursor-protein (APP), ß-amyloid accumulates in the fibers, which display an inflammatory response along with invasion by cytotoxic T-cells. It is unknown whether inflammatory and degenerative pathomechanisms are independent or interrelate with another. The objective is to define the interplay between inflammation, ß-amyloid-associated cell-stress and degeneration in human muscle cells. Based upon preliminary data, we propose the following specific aims to test our central hypothesis that overexpression of APP triggers cell-stress and interrelates with inflammation in muscle: 1) By over-expression of APP in primary human myo-tubes, we expect to identify degeneration-associated conditions that cause a persistent inflamma-tory and cell-stress response; reciprocally, the inflammation is expected to fuel the toxicity of intra-cellular accumulation of ß-amyloid and prevent recovery from cell-stress. 2) Under conditions of cell-stress inflicted by nitric oxide, gene-silencing of APP is anticipated to prevent degeneration of muscle cells caused by ß-amyloid accumulation. The results are expected to substantially add to our knowledge of molecular muscle biology and extend our understanding of the pathology and potential treatment of sIBM as well as of neurodegenerative disorders as Alzheimer¿s dementia.