Project Grant F32AG097046

INVESTIGATING THE INTERFACE BETWEEN EPIGENETICS AND METABOLISM UNDERLYING MEMORY FORMATION IN THE ADULT AND AGING BRAIN - PROJECT SUMMARY AGE-RELATED COGNITIVE DECLINE AND ALZHEIMER'S DISEASE (AD) ARE MASSIVE PUBLIC HEALTH ISSUES, AND CONTINUING TO GROW WITH A 2017 NATIONAL PROJECTIONS REPORT BY THE U.S. CENSUS BUREAU INDICATES THAT IN 2050 THE POPULATION IN THE U.S. AGED 65+ WILL BE APPROXIMATELY 86 MILLION. THESE DECLINES ARE ASSOCIATED WITH MEMORY DEFICITS THAT DECREASE QUALITY OF LIFE FOR THOSE AFFLICTED. THUS, IT IS IMPERATIVE THAT WE CONTINUE TO UNDERSTAND THE MECHANISMS UNDERLYING AGE-RELATED MEMORY PROCESSES. ONE MAJOR KNOWLEDGE GAP IS OUR UNDERSTANDING OF THE EPIGENETIC MECHANISMS NECESSARY FOR REGULATING GENE EXPRESSION DURING MEMORY FORMATION IN THE ADULT BRAIN AS WELL AS THE AGING BRAIN, AND HOW THESE MECHANISMS BECOME DYSFUNCTIONAL IN AD. INCREASING EVIDENCE SHOWS THAT AS WE AGE, THE EPIGENOME BECOMES MORE REPRESSIVE AT SPECIFIC GENES WHICH CONTRIBUTE TO IMPAIRMENTS IN MEMORY PROCESSES. EPIGENETIC MECHANISMS CONTROL EXPRESSION OF GENES WITHOUT ALTERING DNA, PROVIDING THE MECHANISM FOR CELLULAR ADAPTATION. THE WOOD LAB HAS PIONEERED RESEARCH INTO THE EPIGENETICS OF LEARNING AND MEMORY AND HAS IDENTIFIED CREST AS A POTENTIAL POINT OF VULNERABILITY WITH THE CAPACITY TO COORDINATE EPIGENETIC AND METABOLISM MECHANISMS. CREST EXPRESSION DECREASES WITH AGE AND IN BRAINS IMPACTED WITH AD, AND OUR RESEARCH INDICATES THAT CREST REGULATES ACETYL-COA, A CRUCIAL METABOLIC COMPONENT FOR INCREASING GENE ACCESSIBLY AND EXPRESSION. CREST DOES THIS BY TARGETING COMPETING ENZYMES THAT INCREASE (ACSS2) AND DECREASE (ACC1) ACETYL-COA LEVELS. ACETYL-COA HAS BEEN SHOWN TO DECREASE IN AGING AND AD AFFLICTED BRAINS, THUS UNDERSTANDING HOW CREST MAY BE REGULATING ITS PRODUCTION IS VITAL. THEREFORE, CREST MAY BE COORDINATING MECHANISMS THAT PLAY A ROLE IN EXACERBATING AGE- AND AD-RELATED COGNITIVE DYSFUNCTION. THIS PROPOSAL AIMS TO IDENTIFY CREST-DEPENDENT MECHANISMS THAT BECOME DYSFUNCTIONAL IN THE AGING BRAIN AND COULD REVEAL NOVEL THERAPEUTIC TARGETS TO AMELIORATE THE DETERIORATION OF COGNITIVE FUNCTIONS. TO ACCOMPLISH THIS, I WILL USE LEARNING AND MEMORY TASKS, IN CONJUNCTION WITH ADVANCED MOLECULAR ANALYSES. I WILL BI-DIRECTIONALLY REGULATE CREST FUNCTION IN THE HIPPOCAMPUS AND TEST THE IMPACT ON MEMORY CONSOLIDATION IN AGING MICE. I WILL THEN USE NEXT GENERATION SEQUENCING TO ANALYZE CREST BINDING OF THE TARGET GENES IN THE HPC, TO CORRELATE WITH AGE- DEPENDENT MEMORY DEFICITS. FINALLY, THIS PROPOSAL WILL INVESTIGATE ACC1 AS A POTENTIAL THERAPEUTIC TARGET. ACC1 IS A DRUGGABLE ENZYME, THEREFORE I WILL DETERMINE IF REDUCING ITS EXPRESSION CAN RELIEVE MEMORY DEFICITS IN AGED BRAINS. THEREFORE, THE PRIMARY GOAL OF THIS PROPOSAL IS TO DETERMINE IF CREST IS A UNIQUE POINT OF VULNERABILITY IN EXACERBATING AGE-RELATED COGNITIVE DYSFUNCTION.