BME PhD Prospectus Presentation: Dingcheng Sun

Title: "Uncovering Metabolic Signatures of Alzheimer’s Disease Pathology by Chemical Imaging"

Advisory Committee: Timothy O’Shea, PhD - BME, MSE (Chair) Ji-Xin Cheng, PhD - BME, ECE, MSE, Chemistry (Advisor) Lulu Jiang, PhD - Department of Neuroscience, University of Virginia Jerome Mertz, PhD - BME, ECE, Physics Lynne Chantranupong, PhD - Biology Haonan Lin, PhD – BME, Georgia Tech

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder that currently affects over 50 million people worldwide, currently has no effective treatment. AD is driven by the interaction of multiple pathological factors, including apolipoprotein E (APOE) genotype, tau pathology, and amyloid-β accumulation. However, disease phenotypes are determined not only by changes in the abundance of individual biomolecules, but also by their spatial distribution across specific brain cell types and intracellular organelles. How AD pathology disrupts this subcellular metabolic organization remains poorly understood, largely due to the lack of analytical tools that allow the unambiguous characterization of intracellular molecular maps in cells. In this proposal, we aim to reveal how AD-associated genetic and pathological factors generate cell-type- and organelle-specific metabolic signatures and contribute to disease progression using advanced chemical imaging methods. In Aim 1, we will determine how APOE isoforms and tau pathology remodel lipid metabolism in neurons. Considering cellular lipid homeostasis is coordinated by multiple organelles, we will define the spatial and temporal dynamics of metabolic remodeling across mitochondria, lysosomes, lipid droplets (LDs), peroxisomes, and other organelles during AD-associated pathology. In Aim 3, we will extend these measurements to acute brain slice in AD mouse models to characterize lipid accumulation and organelle remodeling across anatomical regions, disease stages, and AD risk genotypes. We will further test whether targeting selected lipid-metabolic abnormalities can reverse pathological phenotype. Together, this work will establish a multiscale, organelle-resolved chemical atlas for AD. By linking organelle-specific molecular composition, this framework will reveal the vulnerability of intracellular organelles to AD-associated pathology and identify organelle-specific metabolic pathways that may serve as targets for therapeutic intervention.