Project Grant RF1AG079176

SEX DIFFERENCES IN EPIGENETIC PARENT-OF-X ORIGIN AND ALZHEIMER'S DISEASE - PROJECT SUMMARY/ABSTRACT BIOLOGIC SEX INFLUENCES ALZHEIMER'S DISEASE (AD). A MAJOR SOURCE OF BIOLOGIC DIFFERENCE BETWEEN THE SEXES IS THAT FEMALES HAVE TWO X CHROMOSOMES AND MALES HAVE ONE. THE SEX-SPECIFIC ROLE OF THE X CHROMOSOME IN INFLUENCING AD IS LARGELY UNKNOWN. THIS GRANT FOCUSES ON X-CHROMOSOME-DERIVED MECHANISMS OF SEX DIFFERENCE USING MOUSE MODELS AND PRIMARY NEURONS COMBINED WITH GENETIC AND EPIGENETIC TOOLS FOR MOLECULAR DISSECTION. UNDERSTANDING THIS UNDERSTUDIED AREA MAY REVEAL NEW X-BASED PATHWAYS THAT COULD ULTIMATELY BENEFIT BOTH SEXES. SEX DIFFERENCES IN AD REVEAL DIFFERING VULNERABILITIES IN MEN AND WOMEN. IN BRIEF, MALE SEX IS A RISK FACTOR FOR RAPID PROGRESSION TO DEATH IN AD. THESE FINDINGS SUPPORT THE FACT THAT MANY MORE WOMEN HAVE AD, DUE IN PART TO THEIR LONGEVITY AND ALSO TO THEIR INCREASED RISK OR INCIDENCE IN OLDER AGE - WHICH TOGETHER CONTRIBUTES TO A HIGHER LIFETIME RISK OF AD IN WOMEN. USING GENETIC MODELS OF SEX BIOLOGY, WE FOUND THAT THE SECOND X CHROMOSOME COUNTERS MORTALITY, DEFICITS AND TOXICITY RELATED TO HAPP/ASS IN BOTH MALE AND FEMALE MICE AND PRIMARY NEURONS. SINCE ONE X INACTIVATES IN FEMALES, X DOSE IS LARGELY SIMILAR BETWEEN THE SEXES. THIS RAISES A KEY QUESTION: WHY WOULD HAVING TWO X'S CONFER ADVANTAGE TO AD-RELATED MEASURES? EACH FEMALE CELL HARBORS TWO X CHROMOSOMES BUT ONE IS SILENCED THROUGH RANDOM X CHROMOSOME INACTIVATION (XCI). XCI INDEPENDENTLY SILENCES ONE X CHROMOSOME IN EVERY XX CELL TO ACHIEVE DOSAGE COMPENSATION OF X EXPRESSION BETWEEN MALE AND FEMALE CELLS. THUS, XX FEMALES ARE MOSAICS WITH THEIR ACTIVE X CHROMOSOMES BEING EITHER MATERNALLY-DERIVED (XM) OR PATERNALLY-DERIVED (XP), WHEREAS MALES HAVE A SINGLE MATERNAL X (XM). A POTENTIAL BENEFIT OF HAVING TWO X'S IS THAT THE DIVERSE COMBINATION OF MATERNAL AND PATERNAL X CHROMOSOMES (XM+XP) COULD BUFFER DELETERIOUS CELLULAR PROCESS RELATED TO AD. WE HYPOTHESIZE THAT XM CONTRIBUTES FUNCTIONAL DEFICITS TO AD PATHOPHYSIOLOGY IN MALES THROUGH EPIGENETIC MECHANISMS - AND THAT MOSAICISM OF THE X (XM+XP) IN FEMALES BUFFERS DEFICITS. SINCE XM AND XP ARE GENETICALLY IDENTICAL IN OUR MODELS, ANY DIFFERENCES BETWEEN THE TWO ARE ATTRIBUTED TO EPIGENETICS. WE WILL PURSUE TWO AIMS: 1. IN AIM 1, WE WILL EXAMINE EPIGENETIC, PARENT-OF-X ORIGIN AND ITS MODULATION OF NEURAL VULNERABILITY TO AD- RELATED DEFICITS IN XX COMPARED TO XY MICE AND CELLS. WE HYPOTHESIZE THAT THE MATERNAL X CHROMOSOME WORSENS NEURAL VULNERABILITY TO AD. 2. IN AIM 2, WE WILL DEFINE HOW SILENCING, OR IMPRINTING, OF THE MATERNAL X CHROMOSOME IMPACTS EACH SEX IN AD-RELATED TOXICITY. WE HYPOTHESIZE THAT THE MATERNAL X SILENCES SELECT GENES IN A CELL-TYPE SPECIFIC MANNER - AND THIS CONTRIBUTES TO SEX-SPECIFIC NEURAL VULNERABILITY. ANSWERS TO OUR QUESTIONS IN XX COMPARED TO XY MICE AND CELLS WILL FUNDAMENTALLY ADVANCE MECHANISTIC UNDERSTANDING OF HOW THE X CHROMOSOME CONTRIBUTES TO SEX DIFFERENCE IN AD, AND WILL LIKELY PAVE X-BASED PATHS TOWARD URGENTLY NEEDED TREATMENTS IN AD, PERSONALIZED FOR MEN, WOMEN, OR BOTH.