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INVESTIGATING LIPID DYSREGULATION ACROSS <EM>APOE4 </EM>GLIAL CELL-TYPES AND DRUG CANDIDATES FOR RESCUING LIPID PATHOLOGY
Alexis Davisonand 9 co-authors
Massachusetts Institute of Technology
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS04-08PM-221
Presentation
Date TBA
Board: PS04-08PM-221
Event Information
Poster Board
PS04-08PM-221
Poster
View posterAbstract
More than 50 million individuals worldwide suffer from dementia with most cases involving Alzheimer’s disease (AD), a neurodegenerative disease resulting in substantial cognitive decline according to the World Health Organization. It estimates this number will continue to increase by 10 million per year if treatments are not discovered. Therefore, it is a pivotal moment in the history of Alzheimer’s disease research. A major genetic risk factor for late-onset Alzheimer’s disease is the APOE4 gene (Corder et al. 1993). APOE encodes apolipoprotein E, a major transporter of lipids and cholesterol in the brain (Mahley 1988). We have previously used isogenic human induced pluripotent stem cell (iPSC)-derived glia to show that APOE4 expression leads to aberrant cholesterol accumulation, reduced uptake of amyloid beta, and lipid droplet accumulation. However, the mechanisms by which APOE4 exerts these effects remains unknown. Therefore, our goal is to identify key factors in the molecular mechanism(s) of these phenotypes by 1) conducting a genome-wide CRISPR knockout screen in APOE4 human iPSC-derived oligodendrocytes, astrocytes, and microglia to determine which genes and pathways are involved in lipid disruption 2) performing high-throughput drug screens among these APOE4 cell types to identify candidates that rescue lipid disruption via analysis of lipid droplet formation. Consequently, we will be presenting the “hit” genes and compounds from both screens that will highlight potential therapeutic targets.
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