Project Grant R43AG084450

EFFECT OF APP COPY NUMBER VARIANTS IN ALZHEIMER'S DISEASE AND AND DOWN SYNDROME ON REELIN EXPRESSION AND FUNCTION - ABSTRACT CHRONIC INFLAMMATORY PATHOLOGY REPRESENTS A MAJOR SOURCE OF DAMAGE TO THE BRAIN OBSERVED IN DOWN'S SYNDROME (DS). ALTHOUGH THE PRECISE ETIOLOGY OF THESE DISEASES IS OFTEN UNKNOWN, EXCESSIVE LEUKOCYTE EXTRAVASATION IS A SUBSTANTIAL CONTRIBUTOR TO THE TISSUE DAMAGE/INFLAMMATION AND OUR RECENT DATA SHOW A PROMINENT ROLE OF THE PLASMA PROTEIN, REELIN IN THIS PROCESS. FURTHERMORE, WE HAVE NOW SHOWN THAT IT IS POSSIBLE, USING ANTI-REELIN MONOCLONAL ANTIBODIES, TO DEPLETE THE PLASMA OF REELIN, WHICH RESULTS IN A SIGNIFICANT REDUCTION OF A WIDE RANGE OF VASCULAR ADHESION MOLECULE EXPRESSION. THUS, IN CONTRAST TO THE CURRENT METHODS OF DEPLETING INDIVIDUAL ADHESION MOLECULES OR IMMUNE RECEPTORS, OUR ANTI-REELIN APPROACH SYSTEMATICALLY DOWNREGULATES ALL MAJOR INFLAMMATION-DRIVEN ADHESION PROTEINS ON THE VASCULAR ENDOTHELIUM. THE PURPOSE OF THIS PROPOSAL IS TO DEMONSTRATE THE ROLE OF REELIN IN DS BY 1) VALIDATING THE THERAPEUTIC POTENTIAL OF MITIGATING CHRONIC INFLAMMATORY MILIEU WITH AN ANTI-REELIN ANTIBODY IN AN DS MOUSE MODEL AND 2) IDENTIFYING HIGH AFFINITY REELIN ANTIBODIES FOR FUTURE THERAPEUTIC DEVELOPMENT.