The overall long-term objective of this FIRST proposal is to understand the molecular pathogenesis of inclusion body myositis (IBM), the most common muscle disease in personals over 50 years of age. Although the cause of this disease remains to be determined, surprisingly it has recently been observed that many of the biochemical features that occur in brains afflicted with Alzheimer's disease also occur in IBM. The Alzheimer's disease brain is characterized by diffuse and neuritic plaques, the hallmark structures of this insidious disease. The principal constituent of these plaques is a small peptide called beta-amyloid. Various histochemical and immunological reagents have been used to show that beta-amyloid deposits accumulate in affected muscle fibers in IBM. Consequently, IBM represents the first disease, other than those disorders related to Alzheimer's disease such as Down syndrome and vascular dementia, where pathological accumulation of the beta-amyloid peptide occurs outside the central nervous system. Notably, the accumulation of beta-amyloid appears to be a specific component of IBM since this peptide is not present in other muscle disorders. This finding is significant and suggests a pathophysiological role for beta-amyloid in this common, age- related myopathy. The observation that beta-amyloid accumulates in inclusion body myositis represents an important opportunity to study the role that this peptide plays in this muscular disorder. For this application, three specific aims are proposed: [1] to investigate the pathophysiological role of beta-amyloid accumulation in skeletal muscle tissue we will derive transgenic mice that selectively over-produce this peptide. The muscle creatine kinase promotor, which has been used by other investigators to direct expression to skeletal muscle of transgenic mice, will be used to specifically target transgenes to these tissues. These mice will allow us to test the hypothesis that beta-amyloid accumulation in muscle leads to pathological changes resembling IBM and provide insights into the pathophysiological role of this peptide in muscle. [2] Another transgenic mouse model will also be derived in which the beta- amyloid pre-cursor protein, the molecule from which beta-amyloid is derived. will be over-produced in muscle; these mice will allow us to test the hypothesis that increased expression of the pre-cursor molecule leads to unmanageable levels of beta-amyloid. Not only would such animal models be useful for studying an age-related muscle disease like IBM, but they may also provide relevant insights into the pathophysiological role these proteins play in Alzheimer's disease as well. [3] Recent evidence from our laboratory suggests that herpes virus, which we found contains a viral protein with shared homology and activity to beta-amyloid, may act as a cofactor for AD. In view of the many parallels between AD and IBM and the prominent role that beta-amyloid plays in IBM, we will investigate in herpes virus may also act as a cofactor in the pathogenesis of IBM.

National Institute of Health (NIH)
National Institute on Aging (NIA)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Molecular Cytology Study Section (CTY)
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Lymn, Richard W
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University of California Irvine
Other Basic Sciences
Schools of Arts and Sciences
United States
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Clinton, Lani K; Blurton-Jones, Mathew; Myczek, Kristoffer et al. (2010) Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci 30:7281-9