Project Grant R01AG086443

UNDERSTANDING THE MECHANISM OF RESCUE OF ALZHEIMERS DISEASE BY HEMATOPOIETIC STEM CELL TRANSPLANTATION - PROJECT SUMMARY ALZHEIMER'S DISEASE (AD) IS THE MOST PREVALENT CAUSE OF DEMENTIA AND THE MOST COMMON AGE-RELATED NEURODEGENERATIVE DISORDER CHARACTERIZED BY THE PROGRESSIVE DEGRADATION OF NEURONS, INFLAMMATION, DECLINE IN MEMORY AND BEHAVIOR, AND THE ACCUMULATION OF B-AMYLOID (AB) PLAQUE IN THE BRAIN, PARTICULARLY IN THE HIPPOCAMPUS AND CORTEX. THE ROLES OF MICROGLIA IN AD ARE STILL A MATTER OF INTENSE DEBATE IN THIS DISEASE. USING THE 5XFAD DOUBLE TRANSGENIC MOUSE MODEL OF AD, WHICH EXPRESSES MUTANT HUMAN APP AND PSEN1, WE DEMONSTRATED THAT SINGLE SYSTEMIC WT HSPC TRANSPLANTATION FULLY RESCUED AD LEADING TO THE PRESERVATION OF MEMORY AND NEUROCOGNITIVE PERFORMANCE, REDUCTION OF THE B-AMYLOID (AB) PLAQUE BURDEN IN HIPPOCAMPUS AND CORTEX, PREVENTION OF MICROGLIOSIS AND NEUROINFLAMMATION, AND PRESERVATION OF THE BLOOD BRAIN BARRIER (BBB) INTEGRITY. WE ALSO SHOWED THAT HSPCS DIFFERENTIATED INTO MICROGLIA-LIKE CELLS IN THE BRAIN, REPLACING UP TO 40% OF THE ENDOGENOUS MICROGLIA IN THE BRAIN AND WITH A RESTING AND RAMIFIED PHENOTYPE. IN CONTRAST, TRANSPLANTING 5XFAD MICE WITH 5XFAD HPSCS HAD LIMITED TO NO IMPACT ON ANY COMPLICATIONS OF AD. THIS WORK OPENS NEW PERSPECTIVES FOR UTILIZING HSPCS FOR THE TREATMENT OF AD. HOWEVER, THE EXACT MECHANISM UNDERLYING THE SIGNIFICANT THERAPEUTIC IMPACT OBSERVED AFTER TRANSPLANTING WT HPSCS IN THE 5XFAD MICE REMAINS UNCLEAR. INDEED, WT HSPC TRANSPLANT FULLY PREVENTED MICROGLIOSIS, NEUROINFLAMMATION AND BBB DISRUPTION, DESPITE PARTIAL REPLACEMENT OF MICROGLIA BY HSPC-DERIVED MICROGLIA-LIKE CELLS, SUGGESTING A SYSTEMIC BENEFICIAL IMPACT OF WT HSPCS. IN CONTRAST, HSPCS ISOLATED FROM 5XFAD MICE EXHIBIT LIMITED TO NO THERAPEUTIC EFFECT, SUGGESTING THAT 5XFAD HSPCS AND/OR THEIR PROGENY CARRY AN INFLAMMATORY PHENOTYPE. THIS WAS SUPPORTED BY OUR PRELIMINARY DATA SHOWING SIGNIFICANT DECREASES IN MEMORY AND INCREASES IN LOCOMOTOR ACTIVITY IN WT MICE TRANSPLANTED WITH 5XFAD HSPCS, RESEMBLING THE BEHAVIORAL PATTERNS OBSERVED IN 5XFAD MICE. WE WILL INVESTIGATE THE MECHANISMS BEHIND THE IMPACT OF HSPCS, BY FIRST ASSESSING THE IMPACT OF 5XFAD HSPCS ON THE MICROGLIOSIS AND NEUROINFLAMMATION IN WT MICE AND BY EXAMINING THE HEMATOPOIETIC LINEAGE PROFILE IN THE PERIPHERAL BLOOD TO VERIFY IF ANY SKEWING TOWARDS A SPECIFIC LINEAGE EXISTS IN THE MICE RECEIVING THE 5XFAD HSPCS. WE WILL ALSO IDENTIFY THE GENETIC SUSCEPTIBILITY THAT MAY EXIST IN 5XFAD HSPCS OR THEIR HEMATOPOIETIC PROGENY USING RNASEQ AND ATACSEQ. IN ADDITION, WE WILL TEST THE POTENTIAL EFFECTS OF MUTATED APP AND/OR PSEN1 ON HEMATOPOIETIC CELL LINEAGES AND DETERMINE WHETHER THEY COULD DIRECTLY TRIGGER A PRO-INFLAMMATORY STATE USING CRISPR/CAS9 TECHNOLOGY TO KNOCKOUT HMAPP AND HMPSEN1 IN MURINE SCA1+ HSPCS. FINALLY, WE WILL DETERMINE THE ABILITY OF WT HSPCS TO REVERSE NEUROINFLAMMATION AND PREEXISTING COMPLICATIONS IN AD DESPITE THE PRESENCE OF AB AGGREGATES BY TRANSPLANTING OLDER 5XFAD MICE (6 MONTHS OF AGE) WITH WT HSPCS. THIS WORK SHOULD SHED LIGHT ON THE UNDERLYING MECHANISMS OF AD RESCUE BY HSPCS, ADVANCE THE UNDERSTANDING THE PATHOGENESIS OF AD, AND EVALUATE THE POTENTIAL OF HSPC-BASED THERAPY FOR THE TREATMENT OF THIS DISEASE.