Research Project
2050614
DESCRIPTION (Adapted from applicant's abstract): Approximately 5 percent of the over 65 population in the US suffers from Alzheimer's disease (AD). Despite its prevalence no efficacious treatments exist. The major histopathological hallmark of AD is amyloid deposition in the brain and cerebrovasculature and its formation may directly participate in the pathogenesis of AD. Amyloid deposition occurs at a frequency about 1000-fold greater than in a normal aged brain. Amyloid is derived from a larger precursor, an isoform of which harbors a Kunitz serine protease inhibitor. Because amyloid appears to be derived via serine proteolytic cleavage, the function of the inhibitor domain and its cognate protease may have a critical role in amyloid development. Recombinant inhibitor has been prepared, characterized, and its tertiary structure determined. This inhibitor will be used to identify, purify, and clone its cognate serine protease. The structure and function of the inhibitor's target protease. The structure and function of the inhibitor's target protease will be evaluated for its potential role in amyloid formation. Detailed physical and biological knowledge of both the inhibitor and its cognate protease may provide a rationale in therapeutic drug development for AD.
