Project Grant R21AG080715

A NOVEL THERAPEUTIC APPROACH FOR ALZHEIMER DISEASE (AD) - PROJECT SUMMARY ALZHEIMER'S DISEASE (AD) IS A CHRONIC NEUROLOGICAL DISORDER CAUSING CELLULAR AND ORGANISMAL METABOLIC DYSFUNCTION, PROGRESSIVE MEMORY DECLINE AND COGNITIVE IMPAIRMENTS. NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD+) IS AN ESSENTIAL METABOLITE THAT IS INVOLVED IN CELLULAR BIOENERGETICS, GENOMIC STABILITY, MITOCHONDRIAL HOMEOSTASIS, ADAPTIVE STRESS RESPONSES, AND CELL SURVIVAL. A GROWING BODY OF EVIDENCE INDICATES THAT NAD+ DECLINE IS ACCOMPANIED WITH PROGRESSION OF AD. IN MAMMALIAN CELLS, THE SALVAGE PATHWAY OF NAD+ BIOSYNTHESIS IS THE PREDOMINANT PATHWAY FOR NAD+ BIOSYNTHESIS, WHERE NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE (NAMPT) IS THE RATE- LIMITING ENZYME. THUS, PHYSIOLOGICAL MEANS TO SYSTEMATICALLY MAINTAIN ELEVATED NAD+ LEVELS TO AUGMENT CELLULAR METABOLIC ACTIVITY IN THE BRAIN MAY REPRESENT AN EFFICIENT ANTI-AD INTERVENTION. RED BLOOD CELLS (RBCS), DIFFERENTIATED FROM HEMATOPOIETIC STEM/PROGENITOR CELLS (HSPCS) IN BONE MARROW (BM) AND RELEASE TO BLOOD CIRCULATION SYSTEM AFTER MATURATION, ARE THE MOST ABUNDANT CELL TYPE IN WHOLE BODY, AND THUS, INCREASE IN NAD+ SYNTHESIS IN THESE CELLS USING GENETIC INTERVENTIONS MAY PROVIDE A PHYSIOLOGICAL MEANS FOR SYSTEMATIC AND SUSTAINED ELEVATION OF NAD+ IN WHOLE BODY THROUGH THE CIRCULATION SYSTEM. HERE WE DEVELOPED AN INNOVATIVE APPROACH, I.E., USING SEROTYPE HELPER-DEPENDENT ADENOVIRUS (HD-AD5) TO OVEREXPRESS NAMPT IN THE RBCS FOLLOWING IN VIVO TRANSDUCTION OF AUTOLOGOUS HSPCS IN MOUSE MODEL. WE HYPOTHESIZE THAT NAMPT OVEREXPRESSION (OE) IN RBCS PROVIDES SYSTEMATIC AND SUSTAINED NAD+ PRODUCTION TO INCREASE METABOLIC ACTIVITY, AND COUNTERACT NAD+ DECLINE IN AD AND AMELIORATE AD CONDITIONS. TO TEST OUR HYPOTHESIS, WE PROPOSE THE FOLLOWING TWO SPECIFIC AIMS. AIM 1 WILL TEST THAT NAMPT OE IN RBCS CAN SYSTEMATICALLY ELEVATES NAD+ LEVELS IN METABOLICALLY ACTIVE ORGANS AND ENHANCES METABOLIC ACTIVITY AT CELLULAR AND ORGANISMAL LEVELS. WE WILL TRANSDUCE HSPCS BY HD-AD5-NAMPT VECTORS CONTAINING NAMPT GENE TO OVEREXPRESS NAMPT IN RBCS AND SUBSEQUENTLY EXAMINE THE NAD+ LEVELS AND METABOLISM IN THE BRAIN AND WHOLE ANIMAL OVER A LONG-TERM PERIOD. AIM 2 WILL TEST THAT NAMPT OE IN RBCS CAN COUNTERACT NAD+ DECLINE AND ALLEVIATE AD PATHOLOGIES IN APP/PS1 AD MOUSE MODEL. USING DIFFERENT METHODS, WE WILL DETERMINE THE EFFECT OF NAMPT OE IN RBCS ON NEURONAL DEGENERATION, AMYLOID SS (ASS) BURDEN, ADULT NEUROGENESIS, COGNITIVE DECLINE, AND DEMENTIA IN AD MOUSE MODEL. THIS APPLICATION IS HIGHLY INNOVATIVE IN CONCEPT, HYPOTHESIS AND APPROACH. TARGETING RBCS USING GENETIC APPROACH FOR THE THERAPY OF GENETIC DISEASES HERE AD OTHER THAN IN THE BLOOD SYSTEM MAY CHANGE GENE THERAPY PARADIGM AND REPRESENTS A NOVEL THERAPEUTIC STRATEGY. OUR PROJECT IS HIGHLY FEASIBLE BASED ON OUR PRELIMINARY DATA, THUS, HAS BOTH SCIENTIFIC AND TRANSLATIONAL SIGNIFICANCES FOR AD AND OTHER BRAIN DISEASES.