Project Grant F30AG094274

DECIPHERING THE ROLES OF APOE4 AND AMYLOID-BETA IN ALZHEIMER'S DISEASE PROGRESSION - PROJECT SUMMARY THE LONG-TERM OBJECTIVE OF THIS WORK IS TO IDENTIFY HOW APOLIPOPROTEIN E (APOE) AND AMYLOID-BETA (AB), TWO KEY PLAYERS IN ALZHEIMER'S DISEASE (AD), CAN BE LEVERAGED AS THERAPEUTIC TARGETS TO TREAT AD. THIS F30 WILL EXAMINE THE DISTINCT ROLES OF APOE AND AB IN DRIVING AD PROGRESSION. AIM 1 WILL STUDY HOW APOE4 DRIVES AB PLAQUES, TAU TANGLES, AND CAA ACROSS THE MOUSE LIFESPAN, AS WELL AS HOW CELLS RESPOND TO THESE PATHOLOGIES. AIM 2 WILL EMPLOY CRE-MEDIATED EXCISION OF AB TO DETERMINE WHETHER HALTING THE PRODUCTION OF AB AFTER PATHOLOGY ARISES IS SUFFICIENT TO SLOW DISEASE PROGRESSION. TOGETHER, THESE INDEPENDENT BUT COMPLEMENTARY AIMS WILL PROVIDE A COMPREHENSIVE UNDERSTANDING OF HOW APOE4 AND AB MODULATE CELLULAR RESPONSES TO AD PATHOLOGIES, UNCOVERING NOVEL TARGETS FOR DISEASE-MODIFYING THERAPIES AND ULTIMATELY IMPROVING PATIENT OUTCOMES. THIS PROPOSAL OFFERS TWO KEY ADVANCEMENTS OVER PREVIOUS WORK IN THE FIELD: (1) IT UTILIZES A NEXT-GENERATION MOUSE MODEL OF AD CALLED MODEL-AD2, WHICH EXPRESSES PHYSIOLOGICAL LEVELS OF THREE KEY HUMAN AD PROTEINS - HUMAN AB, TAU, AND APOE4. THIS IS THE FIRST MOUSE MODEL TO EXPRESS BOTH AB AND TAU PATHOLOGIES IN A SINGLE ANIMAL AT PHYSIOLOGICAL LEVELS, WITHOUT TRANSGENIC MUTATIONS OR OVEREXPRESSION ARTIFACTS. UNLIKE EXISTING MOUSE MODELS OF AD THAT DEVELOP PATHOLOGY TOO EARLY AND IN THE WRONG PLACES, MODEL-AD2 MIRRORS THE SPATIOTEMPORAL DEVELOPMENT OF AD PATHOLOGY IN HUMANS AND EXHIBITS CEREBRAL AMYLOID ANGIOPATHY - A COMMONLY OCCURRING VASCULAR PATHOLOGY IN HUMAN AD. (2) IT EMPLOYS CUTTING-EDGE SINGLE-CELL SPATIAL TRANSCRIPTOMICS TO UNDERSTAND THE ROLES OF APOE AND AB IN DRIVING CELLULAR RESPONSES TO AD PATHOLOGY IN A SPATIALLY RESOLVED MANNER. THIS NOVEL TECHNOLOGY OVERCOMES THE BARRIERS ASSOCIATED WITH PREVIOUS APPROACHES, WHICH EITHER ARE LIMITED TO A FEW TARGETS OR FAIL TO PROVIDE SPATIAL CONTEXT. EXAMINING HOW APOE AND AB MEDIATE CELL-SPECIFIC RESPONSES TO PLAQUES AND TANGLES IN THE NATIVE TISSUE CONTEXT IS CRUCIAL FOR OUR UNDERSTANDING OF AD PROGRESSION AND DEVELOPING TARGETED THERAPIES. THIS PROPOSAL WILL EMPLOY ADVANCED INTEGRATIVE GENOMICS TECHNIQUES TO PROVIDE A COMPREHENSIVE UNDERSTANDING OF THE ROLE OF APOE AND AB IN AD AT BOTH MRNA AND PROTEIN LEVELS. IT WILL ALIGN FINDINGS FROM MOUSE AGING AND GENETIC PERTURBATION STUDIES WITH HUMAN POST-MORTEM DATA, CRITICALLY COMBINING THE STRENGTHS OF THESE TWO SYSTEMS TO IDENTIFY CLINICALLY RELEVANT MOLECULAR TARGETS FOR DISEASE-MODIFYING THERAPIES. THIS PROPOSAL LEVERAGES THE COMPLEMENTARY EXPERTISE OF THE APPLICANT'S SPONSOR, DR. VIVEK SWARUP, AN EXPERT ON UTILIZING UNBIASED MULTI-OMICS APPROACHES AND ADVANCED BIOINFORMATICS ANALYSIS TO UNDERSTANDING THE MOLECULAR UNDERPINNINGS OF NEURODEGENERATIVE DISEASE, AND CO-SPONSOR, DR. KIM GREEN, A GLOBALLY RECOGNIZED AUTHORITY ON MICROGLIA IN AD AND CO-DIRECTOR OF THE NIA-FUNDED MODEL ORGANISMS DEVELOPMENT & EVALUATION OF LATE-ONSET ALZHEIMER'S DISEASE (MODEL-AD) CONSORTIUM AT UCI. THE APPLICANT'S PROPOSAL LIES AT THE INTERSECTION OF DR. SWARUP AND DR. GREEN'S RESEARCH EXPERTISE. TOGETHER, THESE CO-SPONSORS PROVIDE THE APPLICANT WITH THE IDEAL TRAINING ENVIRONMENT TO SUCCESSFULLY COMPLETE THE PROPOSED RESEARCH AND SIGNIFICANTLY ADVANCE THE FIELD OF AD.