EXTRACELLULAR FLUX AND PROTEOME PROFILING REVEAL MOLECULAR INTERPLAY BETWEEN ALZHEIMER’S DISEASE AND INSULIN RESISTANCE
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Alzheimer’s disease (AD) is the leading cause of dementia, a neurodegenerative disorder that brings heavy burden to patients and caregivers. One shared but mechanistically unresolved driver of AD pathology is insulin resistance (IR) as suggested by mounting evidence. This dissertation investigates the molecular and metabolic links between AD and IR with the goal of expanding the limited knowledge of crosstalk between IR-related pathways and AD-associated proteinopathies, to support the eventual development of therapeutic strategies for combating AD and IR. Following the Chapter 1 introduction, Chapter 2 presents a review on existing proteomics studies that contribute to the current understanding of the molecular interplay between AD and type 2 diabetes. Chapter 3 presents a high-throughput extracellular flux profiling assay for characterizing cellular nutrient uptake and excretion on a system level using metabolomics data generated by gas chromatography-mass spectrometry. Chapter 4 applies high-throughput extracellular flux and proteome profiling on established in vitro AD or IR single occurrence models and AD+IR co-occurrence models of primary mouse astrocytes. The results suggest that glycine flux and arginine methylation may serve as molecular links between AD and IR.