Project Grant R01AG089717

GENETICS-INFORMED DISSECTION OF HUMAN BRAIN CELL-CELL COMMUNICATION IN ALZHEIMER'S DISEASE PROGRESSION - ABSTRACT AD IS AN AGE-RELATED NEURODEGENERATIVE DISEASE AND THE LEADING CAUSE OF DEMENTIA IN THE UNITED STATES. IT IS CHARACTERIZED BY A PROGRESSIVE DECLINE OF MEMORY AND COGNITIVE IMPAIRMENT, ULTIMATELY LEADING TO DEMENTIA. CURRENTLY, MORE THAN 5.7 MILLION AMERICANS ARE AFFECTED BY AD, AND THIS NUMBER IS PROJECTED TO BE 16 MILLION BY 2050. ALTHOUGH A TREMENDOUS EFFORT HAS BEEN DEVOTED TO AD RESEARCH, THERE ARE NO EFFECTIVE DISEASE MODIFYING DRUGS AVAILABLE FOR AD, LARGELY DUE TO THE LACK OF UNDERSTANDING OF THE COMPLEX ETIOLOGY OF AD. ALTHOUGH THE ULTIMATE DAMAGE IN AD BRAIN IS NEURONAL LOSS, MULTIPLE CELL TYPES IN BRAIN ARE INVOLVED IN AD DEVELOPMENT AND PROGRESSION. GLIA CELLS, E.G. MICROGLIA AND ASTROCYTES, ARE CRUCIAL FOR BRAIN HEALTHY BRAIN. OTHER CELL TYPES, E.G. VASCULATURE CELLS INCLUDING PERICYTES AND ENDOTHELIA CELLS, THE MAJOR COMPONENTS OF BRAIN-BLOOD BARRIER, AND OLIGODENDROCYTES, WHICH IS RESPONSIBLE FOR MYELINATION OF AXONS, ARE ALL IMPLICATED IN AD. HOW THESE KEY CELL TYPES INTERACT DURING AD DEVELOPMENT, AND IN PARTICULAR HOW GLIA CELLS, E.G. MICROGLIA AND ASTROCYTES, INTERACT WITH NEURONS TO LEAD TO NEURONAL DEATH, ARE POORLY UNDERSTOOD. IN THIS APPLICATION, WE PROPOSE TO DEVELOP NOVEL ANALYTIC APPROACHES TO DISSECT CELL- CELL COMMUNICATION (CCC) AMONG MICROGLIA, ASTROCYTES AND NEURONS, AND HOW THE COMMUNICATIONS ARE DYSREGULATED DURING AD PROGRESSION, AND VALIDATE THE CANDIDATE CCC IN HUMAN IPSC-DERIVED CORTICAL ORGANOIDS. SPECIFICALLY, WE WILL DEVELOP NOVEL NETWORK-BASED MODELS AND STATISTICAL METHODS TO IDENTIFY CCC LINKED TO AD PATHOGENESIS (AIM 1), APPLY THE DEVELOPED METHODS TO ANALYZE PUBLIC SINGLE CELL -OMICS DATA TO IDENTIFY CCC LINKED TO AD PATHOLOGY AND COGNITIVE FUNCTION (AIM 2), AND VALIDATE THE CANDIDATE CCC IN HUMAN IPSC-DERIVED CORTICAL ORGANOIDS TO DECIPHER THE MULTI-CELLULAR COMMUNICATIONS UNDERLYING AD DEVELOPMENT (AIM 3).