Project Grant F31AG094219

UNCOVERING THE PROTECTIVE ROLES OF LXRS IN ALZHEIMER'S DISEASE - PROJECT ABSTRACT ALZHEIMER'S DISEASE (AD) IS A DEVASTATING DISEASE CHARACTERIZED BY PROGRESSIVE LOSS OF MEMORY AND COGNITIVE ABILITIES. ALTHOUGH AD PATHOLOGY AND DISEASE COURSE ARE WELL DEFINED, UNDERLYING DISEASE MECHANISMS ARE NOT UNDERSTOOD. AD PREVALENCE IS INCREASING, YET WE LACK EFFECTIVE TREATMENTS, HIGHLIGHTING THE CRITICAL NEED FOR ADDITIONAL STUDIES TO UNCOVER DISEASE MECHANISMS. TWO HALLMARKS OF AD ARE LIPID ACCUMULATING GLIA AND REACTIVE GLIA, AND WE KNOW THAT GENETIC AD RISK FACTORS ARE ENRICHED IN MUTATIONS THAT IMPACT LIPID METABOLISM AND MICROGLIA FUNCTION. HOW CHANGES IN LIPID METABOLISM AND MICROGLIA FUNCTION CONTRIBUTE TO DISEASE AND WHETHER THESE PROCESSES ACT IN CONCERT TO IMPACT AD IS CURRENTLY UNKNOWN. THE LIVER X RECEPTOR TRANSCRIPTION FACTORS (LXRS) ARE MAJOR REGULATORS OF LIPID METABOLISM AND PROMOTE LIPID EFFLUX BY ACTIVATING EXPRESSION OF LIPID EXPORTER GENES. THESE TRANSPORTERS LIPIDATE APOE, MUTATIONS IN WHICH ARE THE LEADING CAUSE OF SPORADIC AD. ADDITIONALLY, LIVER X RECEPTORS HAVE REPORTED ROLES OF SUPPRESSING INFLAMMATION. DESPITE THE CONNECTION OF LXRS TO LIPID ACCUMULATION AND INFLAMMATION, LITTLE IS KNOWN ABOUT THEIR FUNCTION IN THE BRAIN AND IN THE CONTEXT OF AD. RESULTS FROM A RECENT STUDY SUGGEST ACTIVATING LXRS COULD IMPROVE PATHOLOGY IN AN ALZHEIMER'S DISEASE MOUSE MODEL (P301S/HAPOE4) THAT IS MICROGLIA MEDIATED. MICE TREATED WITH AN LXR AGONIST HAD REDUCED NEURODEGENERATION, SUGGESTING THAT ENHANCING LIPID EFFLUX COULD ALTER MICROGLIA STATES AND BENEFIT DISEASE. THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT IMPAIRED LIPID EFFLUX IN THE BRAIN LEADS TO MICROGLIA ACTIVATION, AND THAT ACTIVATING LXRS PROTECTS AGAINST NEURODEGENERATION IN A TAU MODEL OF NEURODEGENERATION BY MITIGATING MICROGLIA INTERACTIONS WITH T CELLS. AIM 1 WILL USE RNA SEQUENCING AND EPIGENETIC ASSAYS TO DETERMINE HOW GLOBAL LOSS OF LXRS DRIVES INFLAMMATORY GENE EXPRESSION IN MICROGLIA. AIM 1 WILL ALSO REVEAL IF THE LOSS OF LXRS RESULTS IN LIPID ACCUMULATION THAT IS ASSOCIATED WITH INFLAMMATORY MARKER EXPRESSION. AIM 2 WILL USE SEQUENCING APPROACHES AND AN IN VITRO ASSAY TO DEFINE THE MECHANISM BY WHICH LXR AGONIST TREATMENT PROTECTS AGAINST NEURODEGENERATION IN P301S/HAPOE4 MICE. TOGETHER THESE RESULTS WILL UNCOVER POSSIBLE LINKS BETWEEN LIPID METABOLISM AND MICROGLIA INFLAMMATION, AND IN DOING SO, COULD INFORM FUTURE DRUG DISCOVERY EFFORTS.