Project Grant R43AG080911

IMPROVED CARNOSIC ACID CONGENER COMPOUNDS FOR ALZHEIMER?S DISEASE - IMPROVED CARNOSIC ACID CONGENER COMPOUNDS FOR ALZHEIMER'S DISEASE ABSTRACT FIVE MILLION AMERICANS CURRENTLY SUFFER THE DEVASTATING CONSEQUENCES OF ALZHEIMER'S DISEASE (AD), AND UNFORTUNATELY, THE NUMBERS ARE INCREASING DUE TO OUR AGING POPULATION. WHILE SOME TREATMENTS CAN LOWER DISEASE BURDEN, THERE IS NO CURE AND ALL PATIENTS INEVITABLY SUCCUMB. COST OF CARE FOR TREATMENT OF AD IS EXPECTED TO REACH $1.1 TRILLION WITHOUT AN EFFECTIVE TREATMENT OR A CHANGE IN THE TRAJECTORY OF AD. LOSS OF SYNAPTIC FUNCTION IS ASSOCIATED WITH COGNITIVE DECLINE IN AD AND IS A BETTER PREDICTOR OF COGNITIVE LOSS IN AD THAN PLAQUES OR TANGLES. DAMAGE TO NEURONS OCCURS AT LEAST PARTIALLY THROUGH GENERATION OF OXIDATIVE AND NITROSATIVE STRESS, DUE TO EXCESSIVE GENERATION OF REACTIVE OXYGEN/NITROGEN SPECIES (ROS/RNS) TRIGGERED BY OLIGOMERIC AMYLOID BETA (ASS) PEPTIDE AND DOWNSTREAM HYPERPHOSPHORYLATION AND AGGREGATION OF TAU PROTEIN (PTAU). CARNOSIC ACID (CA), A PHENOLIC DITERPENE PARTICULARLY ABUNDANT IN THE HERB ROSEMARY (ROSMARINUS OFFICINALIS), PROTECTS NEURONS AND SYNAPSES FROM DAMAGE CAUSED BY OXIDATIVE STRESS. IN ADDITION TO DIRECT ANTIOXIDANT ACTIVITY, CA BELONGS TO A CLASS OF "PRO-ELECTROPHILES" THAT ACTIVATE THE KEAP1/NRF2 PATHWAY, UPREGULATING TRANSCRIPTION OF A BROAD RANGE OF PHASE II ANTIOXIDANT AND ANTI-INFLAMMATORY PROTEINS THROUGH THE ANTIOXIDANT RESPONSIVE ELEMENT (ARE). IN VITRO, CA PROTECTS NEURONS FROM ASS TOXICITY. CA TREATMENT AMELIORATES VARIOUS BEHAVIORAL AND HISTOLOGICAL DEFICITS IN TRANSGENIC AD MODEL MICE, WHILE SHOWING NO SIGNIFICANT SIDE EFFECTS. DURING THIS PHASE 1 PROJECT, WE WILL DEVELOP A NOVEL, PROPRIETARY CA-DERIVED THERAPEUTIC WITH IMPROVED BIOAVAILABILITY TO ACHIEVE THERAPEUTIC LEVELS WITH ONCE DAILY DOSING. WE WILL THEN EVALUATE THIS NOVEL COMPOUND AS A THERAPEUTIC SMALL MOLECULE FOR THE TREATMENT OF AD.