Project Grant F31AG104751

THE ROLE OF ALZHEIMER'S DISEASE RISK ALLELE APOE4 IN OLIGODENDROCYTE DEVELOPMENT AND FUNCTION - PROJECT SUMMARY ALZHEIMER'S DISEASE (AD) IS A PROGRESSIVE NEURODEGENERATIVE DISORDER THAT AFFECTS MILLIONS WORLDWIDE AND LEADS TO DEGENERATION OF MULTIPLE BRAIN REGIONS, INCLUDING THE HIPPOCAMPUS. THE STRONGEST GENETIC RISK FACTOR FOR LATE- ONSET AD IS THE APOLIPOPROTEIN E4 (APOE4) ALLELE, YET THE MECHANISMS UNDERLYING THIS INCREASED RISK REMAINS POORLY UNDERSTOOD. EMERGING STUDIES HAVE IDENTIFIED EARLY STRUCTURAL CHANGES IN THE BRAINS OF YOUNG APOE4 CARRIERS THAT PRECEDE COGNITIVE IMPAIRMENT, DEFINING A CRITICAL PRECLINICAL STAGE IN WHICH APOE-DRIVEN CHANGES BEGIN TO OCCUR AT THE CELLULAR LEVEL. HUMAN BRAIN IMAGING REVEALS HYPOMYELINATION IN BOTH COGNITIVELY NORMAL ADULT AND PEDIATRIC APOE4 CARRIERS, SUGGESTING THAT MYELIN DYSFUNCTION IS ONE OF THE EARLIEST FEATURES OF THE PRECLINICAL PHASE. MYELIN INSULATES AND SUPPORTS NEURONS AND IS GENERATED BY OLIGODENDROCYTES, WHICH ARISE FROM PROGENITORS KNOWN AS OLIGODENDROCYTE PRECURSOR CELLS (OPCS). OLIGODENDROGENESIS BEGINS AFTER BIRTH AND CONTINUES THROUGHOUT ADULTHOOD TO SUSTAIN MYELIN PLASTICITY AND REMYELINATION. NOTABLY, APOE IS HIGHLY EXPRESSED DURING A PERIOD OF OLIGODENDROCYTE DEVELOPMENT IN BOTH MICE AND HUMANS, YET HOW APOE CONTRIBUTES TO OLIGODENDROCYTE GENERATION AND MATURATION HAS NOT BEEN SYSTEMATICALLY STUDIED. MY PRELIMINARY FINDINGS REVEAL THAT APOE4 IMPAIRS OLIGODENDROCYTE DEVELOPMENT AND DECREASES THE OPC POPULATION IN HUMAN APOE4 KNOCK- IN (KI) MICE COMPARED TO THE NEUTRAL GENOTYPE (APOE3), SUGGESTING THAT THE EFFECTS OF APOE4 MAY START AT THE LEVEL OF THE OPC. I HYPOTHESIZE THAT APOE4 IMPAIRS OPC FUNCTION, REDUCING THE GENERATION OF FUNCTIONAL, MYELINATING OLIGODENDROCYTES DURING DEVELOPMENT AND ADULTHOOD. THIS PROJECT WILL UTILIZE FATE-MAPPING, LINEAGE-TRACING, AND RNA-SEQUENCING APPROACHES TOGETHER WITH HUMAN APOE KI MOUSE MODELS TO INVESTIGATE HOW APOE4 REGULATES OLIGODENDROGENESIS IN TWO AIMS: IN AIM 1 I WILL DETERMINE HOW APOE4 IMPACTS OLIGODENDROCYTE DEVELOPMENT THROUGH CHANGES IN THE CELLULAR AND MOLECULAR PROPERTIES OF OPCS, AND IN AIM 2 I WILL INVESTIGATE HOW APOE4 SHAPES ADULT MYELINATION THROUGH CHANGES IN ONGOING OLIGODENDROGENESIS. THE PROPOSED RESEARCH WILL IDENTIFY EARLY CELLULAR AND MOLECULAR CHANGES THAT CONTRIBUTE TO AD RISK BY DEFINING APOE4-DRIVEN MECHANISMS THAT SHAPE OLIGODENDROCYTE DEVELOPMENT AND MYELINATION. BY TAKING A NEW PERSPECTIVE AND FOCUSING ON THE DEVELOPMENTAL ORIGINS OF APOE4-DRIVEN MECHANISMS THAT DRIVE AD RISK LATER IN LIFE, MY INNOVATIVE PROJECT WILL UNCOVER NEW, EARLY INTERVENTION TARGETS THAT COULD BE DEVELOPED INTO PREVENTATIVE TREATMENTS IN APOE4 CARRIERS. IN ADDITION, THE PROPOSED PROJECT, SUPPORTED BY THE ICAHN SCHOOL OF MEDICINE UNDER THE SUPERVISION OF DR. ALLISON BOND, WILL FOSTER MY PROFESSIONAL GROWTH, MENTORSHIP, TECHNICAL EXPERTISE, AND THE STRONG SCIENTIFIC FOUNDATION I WILL NEED TO ADVANCE MY CAREER GOALS TO BECOME AN INDEPENDENT RESEARCHER STUDYING MECHANISMS OF NEURODEGENERATIVE DISEASE.