Project Grant F30AG099336

SELECTIVE TARGETING OF MYELOID-DERIVED APOE TO IMPROVE SAFETY AND EFFICACY OF ANTI-AMYLOID ANTIBODY THERAPY IN ALZHEIMER'S DISEASE - PROJECT SUMMARY/ABSTRACT: MONOCLONAL ANTIBODIES AGAINST AMYLOID-BETA, SUCH AS LEQEMBI, ARE CURRENTLY THE ONLY APPROVED DISEASE MODIFYING TREATMENTS FOR ALZHEIMER'S DISEASE (AD). IN CLINICAL TRIALS, ONE OF THE PRIMARY ADVERSE EFFECTS OF THESE TREATMENTS WAS THE OCCURRENCE OF AMYLOID RELATED IMAGING ABNORMALITIES (ARIA). ARIA DESCRIBES AN MRI FINDING OF FLUID LEAKAGE OR MICROHEMORRHAGES WHICH CAN BE ASSOCIATED WITH SEVERE SIDE EFFECTS SUCH AS CONFUSION, DELIRIUM, SEIZURES, AND EVEN DEATH. ARIA, AND SYMPTOMATIC ARIA ESPECIALLY, WERE FOUND IN MUCH HIGHER RATES IN CARRIERS OF THE E4 ALLELE OF APOLIPOPROTEIN E (APOE). APOE4 IS THE GREATEST GENETIC RISK FACTOR FOR LATE ONSET AD, WITH CARRIERS OF E4 COMPRISING 60-70% OF PATIENTS WITH AD. CONVERSELY, CARRYING AN E2 ALLELE OF APOE HAS BEEN SHOWN TO BE NEUROPROTECTIVE AGAINST DEVELOPING AD. THERE IS CURRENTLY LIMITED UNDERSTANDING OF THE UNDERLYING MECHANISMS BEHIND ARIA, AND WHY E4 CARRIERS DEVELOP ARIA AT HIGHER RATES. ONE OF THE PRIMARY (BUT UNPROVEN) THEORIES FOR THIS IMPLICATES THE IMMUNE SYSTEM IN DRIVING LOCALIZED INFLAMMATION IN RESPONSE TO ANTI-AMYLOID THERAPY. MICROGLIA AND BORDER ASSOCIATED MACROPHAGES (BAMS) ARE CNS RESIDENT IMMUNE CELLS THAT PLAY KEY ROLES IN RESPONDING TO THIS ANTIBODY THERAPY, PRIMARILY BY CLEARING PLAQUES, DRIVING IMMUNE RECRUITMENT, PROMOTING INFLAMMATION. PREVIOUS STUDIES BY OUR LAB AND OTHERS HAVE IMPLICATED E4 IN DRIVING A MORE PRO-INFLAMMATORY ENVIRONMENT, AS WELL AS HAVING DECREASED CAPACITY FOR PHAGOCYTOSIS, LEADING TO INCREASED PLAQUE ACCUMULATION. FOR THIS REASON, THE PROPOSED WORK WILL TEST THE HYPOTHESIS THAT E4 EXPRESSING MYELOID CELLS DRIVE INCREASED INFLAMMATION AND VASCULAR DYSFUNCTION IN RESPONSE TO ANTI-AMYLOID THERAPY, PRODUCING FINDINGS OF ARIA. WE WILL TEST THIS HYPOTHESIS BY UTILIZING AN INNOVATIVE PRE- CLINICAL MODEL, IN WHICH WE CAN SELECTIVELY REPLACE E4 IN EITHER MICROGLIA OR BAMS, TO TEST CELL SPECIFIC CONTRIBUTIONS TO ARIA. IN SUPPORT, PRELIMINARY STUDIES DONE BY OUR LAB SHOW THAT E4 MICROGLIA ARE MORE ACTIVATED AFTER ANTI-AMYLOID ANTIBODY THERAPY THAN THEIR SALINE OR IGG TREATED COUNTERPARTS, AND THAT A MICROGLIA SPECIFIC SWITCH FROM E4 TO E2 EXPRESSION REDUCES PLAQUE LOAD IN SWITCHED MICE. A BETTER UNDERSTANDING OF THE MECHANISMS OF THESE ANTIBODIES AND HOW E4 DRIVES ARIA IS KEY TO IMPROVING THE SAFETY PROFILE OF THESE DRUGS. THE PROPOSED STUDY WILL UTILIZE A NOVEL CRE-INDUCIBLE MODEL WHICH WILL SELECTIVELY REPLACE E4 IN EITHER BAMS OR MICROGLIA, WHICH WILL ALLOW FOR FURTHER STUDY OF THE EFFECTS OF E4 IN EITHER CELL TYPE ON ARIA. THE PROPOSED STUDY WILL IDENTIFY A POTENTIAL MECHANISM FOR MYELOID DERIVED APOE IN ANTIBODY MEDIATED PLAQUE CLEARANCE AND ADVERSE EFFECTS FOR PATIENTS AT HIGHEST RISK OF AD. MORE SPECIFICALLY, THIS APPROACH WILL IDENTIFY CELL-SPECIFIC CONTRIBUTIONS OF MICROGLIA OR BAM DERIVED E4 TO ARIA PATHOGENESIS. THE EXPERIMENTAL PLAN WILL UTILIZE CUTTING EDGE PRECLINICAL MODELING, AS WELL AS MULTI-OMICS APPROACHES TO PROVIDE NOVEL INSIGHTS INTO THE ROLE OF MYELOID APOE WHILE PROVIDING THE PI A FOUNDATION FOR APPROACHING CLINICAL QUESTIONS WITH PRECLINICAL MODELING IN PREPARATION FOR A FUTURE CAREER AS A PHYSICIAN-SCIENTIST.