Project Grant R21NS133527

TARGETING TREM2 AD/ADRD RISK AND IMMUNOMETABOLISM IN HUMAN MICROGLIA - PROJECT SUMMARY TRAUMATIC BRAIN INJURY (TBI) AND ALZHEIMER'S DISEASE (AD) CAUSE LONG-TERM DISABILITY AND DEMENTIA THAT AFFLICT MILLIONS OF INDIVIDUALS. BOTH TBI AND HYPOMORPHIC VARIANTS OF TREM2, A GENE EXCLUSIVELY EXPRESSED BY MICROGLIA IN THE BRAIN, INCREASE SPONTANEOUS AD RISK. HIGH MOBILITY GROUP BOX 1 (HMGB1) PROTEIN IS A PROTEIN THAT INCREASES EXTRACELLULARLY WITH AGE AND FOLLOWING TBI THAT INITIATES PRO-INFLAMMATORY SIGNALING IN MICROGLIA, THE INNATE IMMUNE CELLS OF THE BRAIN. THIS PROPOSAL WILL TEST THE CENTRAL HYPOTHESIS THAT IDEBENONE RESTORES ASS PHAGOCYTOSIS CAPACITY AND THE BASELINE AND HMGB1-REACTIVE TRANSCRIPTOMIC SIGNATURES OF TREM2-DEFICIENT HUMAN MICROGLIA BY RESCUING MITOCHONDRIAL BIOENERGETIC FUNCTION. TREM2 IS REQUIRED FOR HOMEOSTATIC FUNCTIONS OF MICROGLIA, INCLUDING THEIR PHAGOCYTIC CAPACITY FOR CLEARING AMYLOID-SS (ASS) AGGREGATES LINKED TO AD PATHOLOGY. HOWEVER, BECAUSE DEFICIENT TREM2 SIGNALING IS ONLY A RISK FACTOR, LIFETIME ENVIRONMENTAL FACTORS, WHICH MAY INCLUDE TBI AND AGE-ASSOCIATED CHANGES, ARE REQUIRED FOR AD MANIFESTATION. METABOLIC ALTERATIONS IN RESPONSE TO EXOGENOUS CUES REWIRE HOW VARIOUS IMMUNE CELL TYPES, INCLUDING MICROGLIA, INTERACT WITH THEIR ENVIRONMENT. THE PRIMARY GOALS OF THIS PROPOSAL ARE TO: I) ELUCIDATE SITE(S) OF MITOCHONDRIAL RESPIRATORY CHAIN IMPAIRMENT IN HUMAN INDUCED PLURIPOTENT STEM CELL (IPSC)-DERIVED MICROGLIA-LIKE CELLS THAT ARE TREM2 SIGNALING-DEFICIENT, II) DETERMINE WHETHER THE CLINICALLY SAFE COMPOUND IDEBENONE RESCUES MITOCHONDRIAL BIOENERGETIC FUNCTION, THE TRANSCRIPTIONAL RESPONSE TO AGING/TBI-RELEVANT HMGB1 STIMULATION, OR IMPAIRED ASS PHAGOCYTOSIS IN HUMAN TREM2-DEFICIENT MICROGLIA-LIKE CELLS (HEREAFTER REFERRED TO SIMPLY AS MICROGLIA), III) BEGIN TO EVALUATE INDIVIDUAL HUMAN VARIABILITY IN MALE AND FEMALE MICROGLIAL RESPONSES TO TBI- AND AD-RELEVANT INFLAMMATORY STIMULATION, AND IV) BEGIN TO EVALUATE INDIVIDUAL VARIABILITY IN THE ABILITY OF HUMAN MICROGLIA TO ENZYMATICALLY REDUCE IDEBENONE TO ITS ACTIVE FORM, IDEBENOL. THESE GOALS LOGICALLY BUILD ON THE LAB'S PREVIOUS LINES OF INVESTIGATION BY EVALUATING TBI- RELEVANT MICROGLIAL IMMUNE RESPONSES IN TANDEM WITH A GENETIC AD RISK FACTOR IN HUMAN CELLS AND TESTING WHETHER A CLINICALLY SAFE MITOCHONDRIA-TARGETED INTERVENTION MITIGATES IMMUNOMETABOLIC "PROGRAMMING" DEFICITS RELEVANT TO AD AND AD-RELATED DEMENTIAS (ADRD). AIM 1 WILL TEST THE PREDICTIONS THAT THE MITOCHONDRIAL DEFECT(S) OF TREM2 DEFICIENT IPSC-DERIVED MICROGLIA OCCUR UPSTREAM OF RESPIRATORY CHAIN COMPLEX III AND CAN BE RESCUED BY IDEBENONE. AIM 2 WILL TEST THE PREDICTIONS THAT IDEBENONE NORMALIZES BOTH THE BASELINE AND HMGB1-STIMULATED TREM2-DEFICIENT HUMAN MICROGLIAL TRANSCRIPTOMIC SIGNATURES AND THE RATE OF PHAGOCYTIC ASS CLEARANCE. OUR STUDIES WILL DETERMINE SPECIFIC UNDERLYING MECHANISM(S) OF MITOCHONDRIAL BIOENERGETICS DEFICITS IN HUMAN MICROGLIA WITH DEFICIENT TREM2 SIGNALING, POTENTIALLY REVEALING NOVEL INTERVENTION STRATEGIES TO FORESTALL AD DEVELOPMENT DUE TO GENETIC RISK OR ENVIRONMENTAL FACTORS LIKE TBI. IN ADDITION, OUR STUDIES WILL BEGIN TO ADDRESS HOW INDIVIDUAL GENETIC VARIABILITY INFLUENCES THE USE OF IDEBENONE AS A TREATMENT STRATEGY.