Project Grant F31AG104483

TARGETING BRAIN-INTRINSIC IMMUNE CHECKPOINT SIGNALING TO RESTORE NEUROPROTECTIVE GLIOSIS IN ALZHEIMER'S DISEASE - PROJECT SUMMARY/ABSTRACT IMMUNE SIGNALING IS A FUNDAMENTAL REGULATORY SYSTEM THAT MAINTAINS TISSUE HOMEOSTASIS, PROTECTS AGAINST PATHOGENS, AND RESOLVES INFLAMMATION ACROSS NEARLY EVERY ORGAN SYSTEM. A KEY COMPONENT OF THIS REGULATION INVOLVES IMMUNE CHECKPOINT PATHWAYS-RECEPTOR-LIGAND INTERACTIONS THAT ACT AS MOLECULAR "BRAKES" TO RESTRAIN OVERACTIVE IMMUNE RESPONSES AND PRESERVE SELF-TOLERANCE. WHILE EXTENSIVELY STUDIED IN PERIPHERAL TISSUES AND IN THE CONTEXT OF CANCER, WHERE TUMOR CELLS UPREGULATE CHECKPOINT LIGANDS TO EVADE IMMUNE CLEARANCE, THE FUNCTION OF THESE PATHWAYS WITHIN THE CENTRAL NERVOUS SYSTEM IS ONLY BEGINNING TO BE UNDERSTOOD. CURRENTLY, PERIPHERAL INFILTRATING IMMUNE CELLS ARE SUGGESTED TO PLAY A ROLE IN LATE-STAGE AD PATHOLOGY IN MICE, IN PART THROUGH DYSREGULATED PD-1/PD-L1 SIGNALING. HOWEVER, CNS-RESIDENT CELLS ALSO EXPRESS THESE CHECKPOINT MOLECULES, AND THE CONTRIBUTION OF THIS BRAIN-INTRINSIC SIGNALING HAS NOT BEEN THOROUGHLY INVESTIGATED. RECENT STUDIES HAVE IDENTIFIED IMMUNE CHECKPOINT RECEPTOR-LIGAND PAIRS, SUCH AS PD-1 AND PD-L1, IN CNS-RESIDENT GLIAL CELLS, SUGGESTING THEY MAY MODULATE NEUROINFLAMMATION AND GLIAL ACTIVATION. ALZHEIMER'S DISEASE (AD), CHARACTERIZED BY THE PROGRESSIVE ACCUMULATION OF NEUROFIBRILLARY TANGLES, AMYLOID-BETA (AB) PLAQUES, AND CHRONIC NEUROINFLAMMATION, IS THE LEADING CAUSE OF DEMENTIA IN THE WORLD. EMERGING WORK IN AD MOUSE MODELS SUGGESTS THAT ABERRANT ASTROCYTIC PD-L1 SIGNALING DISRUPTS MICROGLIAL DYNAMICS AND CONTRIBUTES TO AB PATHOLOGY AND RELATED CELLULAR CONSEQUENCES. WHILE THIS BOLSTERS THE NOTION OF BRAIN-INTRINSIC IC SIGNALING, THE PRECISE SPATIOTEMPORAL EXPRESSION PATTERN OF PD-1/PD-L1 IN RESPONSE TO THE ONSET AND PROGRESSION OF AD PATHOLOGY REMAINS UNCLEAR. OUR RESEARCH WILL ADDRESS THIS GAP BY UTILIZING A NEW AD MOUSE MODEL FEATURING AB AND TAU DEPOSITS, AS WELL AS AAV-BASED GENETIC MANIPULATION, TO CHARACTERIZE THE ROLE OF PD-1/PD-L1 SIGNALING. ADDITIONALLY, WE WILL TEST BBB- PENETRANT ANTI-PD-L1 ANTIBODIES TO RESTORE GLIAL FUNCTION AND IMPROVE AD OUTCOMES. WE WILL EXPLORE OTHER PREDICTED CHECKPOINT SIGNALING PAIRS AND VALIDATE ALL FINDINGS IN HUMAN AD BRAIN SAMPLES. ALTOGETHER, WE HYPOTHESIZE THAT BRAIN-INTRINSIC IMMUNE CHECKPOINT SIGNALING BECOMES ABERRANTLY ACTIVATED IN RESPONSE TO AD PATHOLOGY, RESULTING IN MALADAPTIVE GLIAL PHENOTYPES THAT PROMOTE DISEASE PROGRESSION. COMPLETION OF THIS PROPOSAL WILL SHED LIGHT ON HOW IMMUNE CHECKPOINT SIGNALING CONTRIBUTES TO GLIAL-MEDIATED DYSFUNCTION IN AD AND PROVIDE A RICH SPATIAL DATASET THAT CAN BE LEVERAGED FOR FURTHER MECHANISTIC STUDIES. AN INCREASED UNDERSTANDING OF THE IMPACT OF CHECKPOINT PATHWAYS ON GLIA AND AD PATHOLOGY WILL BE CRUCIAL FOR THE DESIGN OF IMMUNOMODULATORY THERAPEUTICS TARGETING BRAIN-INTRINSIC IMMUNE REGULATION IN AD. THE UCSF INSTITUTE FOR NEURODEGENERATIVE DISEASES (IND) PROVIDES AN IDEAL ENVIRONMENT FOR COMPLETING THE PROPOSED WORK, OFFERING RIGOROUS TRAINING IN SPATIAL TRANSCRIPTOMICS, ADVANCED IMAGING, AND BIOINFORMATICS, AS WELL AS SUPPORT FOR PROFESSIONAL DEVELOPMENT. FURTHERMORE, MY SPONSORS ARE COMMITTED TO THE COMPREHENSIVE TRAINING PLAN WE HAVE DEVELOPED, WHICH WILL PREPARE ME FOR A CAREER AS A SCIENTIFIC LEADER IN NEUROIMMUNOLOGY AND NEURODEGENERATION RESEARCH.