Abstract

This proposal is based on our new findings that Alzheimer-like beta-amyloid protein betaAP is abnormally accumulated in vacuolated muscle fibers of patients with Sporadic (S) and Hereditary (H) Inclusion-Body Myositis (IBM). Heretofore, abnormalities in the brain involving betaAP accumulation were considered exclusive for Alzheimer's disease, Down syndrome, Dutch-type hereditary cerebrovascular amyloidosis and very advanced age. betaAP expression in normal and diseased human muscle has not been studied. The broad objective of our research is to utilize human muscle tissue-culture models for multidisciplinary molecular biology studies of the role of betaAP and its precursor protein (betaAPP). The long-term goals are to ascertain the role of betaAP in human muscle during: a) muscle necrosis; b) normal development, maturity and aging; c) development and maintenance of neuromuscular synapses.
Specific Aims : 1. Establish whether betaAP will be abnormally accumulated in cultured muscle fibers of patients with a hereditary and sporadic IBM (in both betaAP is accumulated in the biopsied muscle). 2. Delineate whether development in culture of the morphologic phenotype characteristic of IBM correlates with an abnormal accumulation of betaAP and other betaAPP sequences. 3. Establish in cultured IBM muscle the sequence of developmental expression of the betaAPP gene, and accumulation of betaAP and possibly other betaAPP sequences. 4. Establish whether exogenously applied betaAP is toxic to cultured normal human muscle. This study is expected to establish whether: a) abnormal accumulation of betaAP in H-IBM is genetically determined; b) there is increased expression of the betaAPP gene in cultured H-IBM muscle; c) betaAP is toxic to human muscle and whether it produces the IBM phenotype. Because the pathologic accumulation of betaAP in IBM muscle and in AD brain have many similar features, their pathogeneses may share similar mechanisms. It is possible that the characteristic muscle degeneration occurring in IBM may represent a specific form of muscle aging, with similarities to brain aging in the Alzheimer phenotype. Accordingly, detailed molecular studies of pathogenic mechanisms in the more readily accessible biopsied living IBM muscle (as compared to brain), including use of cultured H-IBM muscle, might contribute to understanding AD.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS031836-02
Application #
2269793
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1993-04-01
Project End
1996-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
University of Southern California
Department
Neurology
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089