Project Grant F30AG104716

THERAPEUTIC POTENTIAL OF PU.1 IN ALZHEIMER'S DISEASE - PROJECT SUMMARY/ABSTRACT ALZHEIMER'S DISEASE (AD) IS THE LEADING CAUSE OF DEMENTIA, ACCOUNTING FOR AROUND TWO-THIRDS OF ALL DEMENTIA CASES, YET EFFECTIVE TREATMENT OPTIONS REMAIN LIMITED. AD IS CHARACTERIZED BY CHRONIC NEUROINFLAMMATION, AGGREGATION OF EXTRACELLULAR AMYLOID-BETA (AB) PLAQUES, AND NEUROFIBRILLARY TANGLES, WHICH ARE INTRANEURONAL DEPOSITIONS OF HYPER-PHOSPHORYLATED TAU. MULTIPLE GENETIC STUDIES ON AD HAVE IDENTIFIED KEY IMMUNE PATHWAYS AS CONTRIBUTORS TO AD, POINTING TO MICROGLIA, THE BRAIN'S RESIDENT IMMUNE CELLS, IN PLAYING A KEY ROLE IN DRIVING DISEASE PROGRESSION. UNDER PATHOLOGICAL CONDITIONS, MICROGLIAL HOMEOSTASIS BECOMES DYSREGULATED, COMPROMISING BOTH SURVEILLANCE FUNCTIONS AND APPROPRIATE INFLAMMATORY RESPONSES. HOWEVER, OUR UNDERSTANDING OF HOW TO MODULATE MICROGLIAL FUNCTION IN AD IS STILL LIMITED. WHILE PREVIOUS AD STUDIES HAVE TRADITIONALLY FOCUSED ON A SINGLE GENETIC TARGET IDENTIFIED THROUGH GENOME-WIDE ASSOCIATION STUDIES, WE INSTEAD AIM TO INVESTIGATE HOW MULTIPLE AD PATHWAYS CONVERGE AND ARE REGULATED. OUR STUDY FOCUSES ON PU.1, A MASTER TRANSCRIPTION FACTOR KNOWN TO REGULATE MULTIPLE AD RISK GENES AND CONTROL MICROGLIAL FUNCTION. CRITICALLY, THE THERAPEUTIC DIRECTIONALITY OF PU.1 HAS NOT YET BEEN ELUCIDATED IN A CLINICALLY RELEVANT MOUSE MODEL THAT RECAPITULATES BOTH AMYLOID AND TAU PATHOLOGY. OUR CENTRAL HYPOTHESIS IS THAT PU.1 MODULATES AMYLOID AND TAU PATHOLOGY VIA KEY MICROGLIAL GENES THAT MAY LATER BE TARGETED FOR THERAPEUTICS. TO TEST THIS, WE WILL USE TWO COMPLEMENTARY APPROACHES. FIRST, WE WILL EXAMINE HOW PHARMACOLOGICAL INHIBITION OF PU.1 ALTERS AD NEUROPATHOLOGY AND MICROGLIAL FUNCTION IN A COMBINED AMYLOIDOSIS-TAUOPATHY MOUSE MODEL. SECOND, WE WILL IDENTIFY PU.1 TARGET GENES THAT CONTRIBUTE TO FUNCTIONAL RESCUE OF MICROGLIAL PHAGOCYTOSIS AND INFLAMMATORY RESPONSE DESPITE PU.1 SUPPRESSION, USING HUMAN INDUCED MICROGLIAL-LIKE CELLS. TOGETHER, OUR PROJECT WILL HELP DEFINE THE THERAPEUTIC DIRECTIONALITY OF PU.1 IN AN AD-LIKE MOUSE MODEL AND POTENTIALLY IDENTIFY PU.1 TARGET GENES THAT CAN RESCUE MICROGLIAL FUNCTION. BY FOCUSING ON PU.1'S ROLE IN MICROGLIAL REGULATION AND IMMUNE RESPONSES, OUR RESEARCH WILL PROVIDE NEW INSIGHTS INTO THE CONVERGING IMMUNE PATHWAYS THAT UNDERLY NEURODEGENERATION.