STRUCTURE AND FUNCTION OF ALZHEIMER'S DISEASE PROTEASE INHIBITOR

APPROXIMATELY 5 PERCENT OF THE POPULATION OVER AGE 65 IN THEUNITED STATES SUFFERS FROM ALZHEIMER'S DISEASE (AD). DESPITE ITS PREVALENCE, NO EFFICACIOUS TREATMENTS EXIST. DEFINITIVE DIAGNOSIS IS MADE ON AUTOPSY USING THE HISTOPATHOLOGICAL HALLMARK OF THE DISEASE-AMYLOID DEPOSITIONIN THE BRAIN AND CEREBROVASCULAR SYSTEM. AMYLOID DEPOSITION OCCURS IN AD AT A FREQUENCY 1,000-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 PRODUCE A RECOMBINANTLY 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. STRUCTURALAND FUNCTIONAL KNOWLEDGE MAY PROVIDE A RATIONALE FOR THERAPEUTIC INTERVENTION IN AD.