Project Grant R01AG088199

ACTIVATED PROTEIN C SIGNALING IN AGING - PROJECT SUMMARY ALZHEIMER'S DISEASE (AD) IS THE MOST COMMON FORM OF DEMENTIA AND IS BECOMING A NATIONAL HEALTH CRISIS AS THE SIXTH LEADING CAUSE OF DEATH IN THE UNITED STATES. PROMINENT BEHAVIORAL MANIFESTATIONS OF AD INCLUDE MEMORY LOSS AND COGNITION WITH THE PATHOLOGICAL HALLMARK OF THE EXTRACELLULAR AMYLOID BETA (A) PLAQUES AND INTRANEURONAL DEPOSITS OF NEUROFIBRILLARY TANGLES (NFTS) ACCUMULATION. AMONG THAT, A ACCUMULATION IS PROPOSED TO INITIATE THE AD VIA DAMAGING SYNAPSES AND NEURONS. HOWEVER, THERAPEUTICS TARGETING ON AB HYPOTHESIS WERE FOUND TO HAVE LITTLE SUCCESS. THEREFORE, IDENTIFYING NOVEL MOLECULAR AND CELLULAR FACTORS UNDERLYING THE PATHOGENESIS OF AD IS URGENT IN DEVELOPING EFFECTIVE THERAPIES. ONE OF THE IMPORTANT RISK FACTORS FOR AD IS AGING WHICH IS ASSOCIATED WITH BIOENERGETIC DEFICITS, OXIDIZED REDOX ENVIRONMENT, AND CHRONIC INFLAMMATION THAT LEADS TO SYNAPSE DYSFUNC- TION AND NEURON DAMAGE. OUR PRELIMINARY STUDY SHOWED THAT A NOVEL AGE-RELATED PROTEIN, ACTIVATED PROTEIN C (APC) PLAYS A KEY ROLE IN THE PATHOGENESIS OF AD VIA MODULATING THE METABOLIC AND REDOX HOMEOSTASIS IN THE BRAIN. APC IS A PLASMA PROTEASE EXERTING ANTICOAGULANT AND CYTOPROTECTIVE EFFECTS, INCLUDING MODULATING META- BOLIC PATHWAYS, REPRESSING INFLAMMATION, AND PROTECTING NEURONS FROM STROKE AND TRAUMA. INTRIGUINGLY, WE FOUND THAT THE DEPLETION OF APC IN MICE RESULTS IN AGING-LIKE CARDIAC DYSFUNCTION AND AD-LIKE COGNITIVE DEFICIT SYMPTOMS. RECOMBINANT APC CAN BLOCK THE DEPOSITION OF AMYLOID PLAQUE, IMPROVES COGNITIVE BEHAVIOR, AND AMELIORATES THE CARDIAC DYSFUNCTION OBSERVED IN AD MODEL MICE. OUR LONG-TERM OBJECTIVE IS TO UNDERSTAND THE ROLES AND MECHA- NISMS OF APC IN AD PATHOGENESIS TO DEVELOP AN EFFECTIVE THERAPEUTIC STRATEGY FOR THE ELDERLY WITH AD. AT THE MECHANISTIC LEVEL, APC DEPLETION INDUCES THE DERANGEMENT OF METABOLIC AND REDOX HOMEOSTASIS IN THE BRAIN WHILE APC TREATMENT TRIGGERS ACTIVATED PROTEIN KINASE B (AKT) SIGNALING WHICH STIMULATES GLUCOSE METABOLIC RATE, REPRESSES CELLULAR INFLAMMATORY SIGNALING, AND REDUCES AMYLOID PLAQUES IN AD. THEREFORE, WE HYPOTHESIZE THAT APC PLAYS A CRITICAL ROLE IN PROTECTING NEUROFUNCTION THROUGH MAINTAINING METABOLIC HOMEOSTASIS AND REPRESSING NEUROINFLAMMATORY RESPONSES AGAINST AD PATHOGENESIS. THIS HYPOTHESIS WILL BE TESTED BY FOLLOWING TWO SPECIFIC AIMS: 1) TO CHARACTERIZE THE ROLE OF APC SIGNALING IN THE PATHOGENESIS OF AD. 2) TO ELUCIDATE THE CAPABILITY OF APC DERIVATIVES TO IMPROVE NEUROFUNCTION AGAINST AD. IN ADDITION, WE WILL DETERMINE IF THE ANTICOAGULANT DOMAIN OF APC IS IMPORTANT FOR ITS NEUROPROTECTIVE FUNCTION TO PROVIDE EVIDENCE THAT RECOMBINANT APC WITHOUT ANTICOAG- ULANT ACTIVITY CAN BE USED FOR THERAPY OF ALZHEIMER'S DISEASE WITHOUT THE RISK OF BLEEDING.