STRUCTURE/FUNCTION ALZHEIMERS DISEASE PROTEASE INHIBITOR

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Approximately 5% of the over 65 population in the U.S. suffers from Alzheimer's disease (AD). Despite its prevalence no efficacious treatment exist. Definitive diagnosis is made on autopsy using the histopathological hallmark of the disease - amyloid deposition in the brain and cerebrovasculature. Amyloid deposition occurs at a frequency 1000-fold greater than in a normal aged brain. Amyloid is derived from a larger precursor protein, an alternative form of which harbors a Kunitz protease inhibitor. Because amyloid is derived via proteolytic cleavage, the function of the inhibitor domain may have a critical role in both the normal and pathological condition. The aim of phase I is to recombinantly produce homogeneous inhibitor suitable for three-dimensional structural analysis. Phase II will be aimed at resolving the tertiary structure of the inhibitor, identifying its target protease, and determining its functional role in the proteolytic processing of the amyloid precursor. Structural and functional knowledge may provide a rationale for therapeutic intervention in AD.