Dysregulated cholesterol metabolism in Alzheimer's Disease astrocytes: Investigating contributions to neuronal dysfunction

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Project Summary The absence of effective therapies to slow or prevent progression have made Alzheimer’s Disease (AD) a global health crisis. Inflammation, neuronal dysfunction, and eventual neuronal loss are hallmarks of AD. Cholesterol metabolism is also implicated in AD and other neurodegenerative diseases. For example, accumulation of lipid droplets that store intracellular lipids are observed in AD brains. Cholesterol acts as a signaling molecules and is an essential component of biological membranes. Notably, cholesterol levels in the presynaptic and postsynaptic compartments influence synaptic transmission. Thus, changes to cholesterol metabolism could directly induce neuronal dysfunction and other AD-associated pathology. While most research focuses on neurons, non-neuronal glial cells are essential in regulating neuronal function and maintaining brain homeostasis. Astrocytes are a class of glial cell that interact with synapses, blood vessels, and other glial cells, playing essential roles in the regulation of synaptic connectivity and function throughout life. Recent studies suggest that changes to astrocytes are potential drivers of AD pathology. Astrocytes have decreased physiological functions and release inflammatory factors in disease states. As the main producers of cholesterol in the brain, cholesterol dysregulations in AD could also be primarily driven by changes in astrocyte metabolism. However, it is still unclear to what extent cholesterol metabolism is dysregulated in AD astrocytes and what specific genes could be targeted to reverse these changes. The overall goal of my dissertation and post-doctoral research is to characterize cholesterol metabolism in astrocytes in the context of AD. Preliminary data in Aim 1 demonstrates my ability to use human stem cell models to study intrinsic changes in astrocytes derived from individuals with AD using multi-omic and metabolomic approaches. In Aim 1, I propose taking a closer look at how cholesterol is dysregulated in AD astrocytes and how these dysregulations promote AD-related astrocyte dysfunctions, such as adoption of neurotoxic properties and loss of the ability to support neurons. During the K00 Phase, I propose expanding these analyses to in vivo models to probe system-wide contributions of astrocyte cholesterol metabolism. The Training Plan integrates scientific and professional development activities that will advance my long- term career goals of becoming an independent neuroscience researcher and principal investigator of an academic laboratory. The proposed research provides ample opportunities for developing technical expertise in astrocyte biology, metabolism, and analytical techniques. My Sponsors will be instrumental in helping me build skills in experimental design, scientific communication, and grantsmanship. They will also guide me in finding a postdoctoral training environment that aligns with my long-term research and career goals.