Dissertation Defense: Yi (Emma) Lu

"The Role of RXR - ABCA1 - APOE regulatory axis in Alzheimer's Disease: Transcriptional and Metabolic Remodeling of Microglial and Astrocytic Responses to Amyloid Pathology" School of Public Health Department of Environmental and Occupational Health. Committee: Nicolas Fitz, chairIliya LefterovAaron BarchowskyJiebiao WangRadosveta Koldamova, dissertation advisorAbstract: Lipid-metabolic dysfunction and neuroinflammation are increasingly recognized as central drivers of Alzheimer's disease (AD) pathology. ABCA1, an ATP-binding cassette transporter regulating lipid efflux and APOE lipidation, and RXR/LXR nuclear receptors, which coordinate lipid sensing and metabolic adaptation, represent convergent nodes controlling metabolic and inflammatory glial responses to amyloid pathology. This thesis investigates how the ABCA1–RXR–APOE axis functionally integrates lipid-metabolic and neuroinflammatory remodeling in microglia and astrocytes. We first performed integrated scRNA-seq, snATAC-seq, ChIP-seq, and transcription factor footprinting on APP/PS1 mice treated with the RXR agonist bexarotene. RXR activation initiated hierarchical transcriptional cascades: direct RXR binding at accessible chromatin recruited secondary transcription factors (Nfatc2, Egr1, Creb3l2), which propagated through tertiary networks controlling lipid metabolism and stress responses. Then, we examined ABCA1 deficiency using scRNA-seq on microglia and astrocytes from APP/PS1 mice, integrated with lipidomics and proteomics approaches. Loss of ABCA1 remodeled the microglial landscape, expanding disease-associated microglia (DAM) population through both additive effects and context-dependent synergistic transcriptional programs. ABCA1 insufficiency suppressed biosynthetic and ribosomal programs while sustaining inflammatory activation. Astrocytes responded through distinct transcriptional remodeling of lipid export pathways, revealing a cellular division of labor wherein microglia sense lipid availab