Investigating Alzheimer’s Disease-Associated Membrane Biology in Microglia and Neurons

Alzheimer’s disease (AD) is associated with changes in the brain’s lipid abundance and composition. This likely changes the properties of brain cells, but the unexplored diversity of lipids and the paucity of well-established lipid biology tools have limited our understanding of the cellular responses to lipids in AD. In our previous work with Cure Alzheimer’s Fund, we applied FALCON (Fatty Acid Library for Comprehensive Ontologies), a platform for interrogating 61 structurally diverse lipids, to the study of microglia. Microglia are key cellular players in the pathogenesis of AD, but the interplay between microglia and lipids remains an open question. FALCON revealed a specific set of lipids that induce morphological changes in microglia, cause cell stress, and ultimately lead to death. Building on what we learned from our previous CureAlz-funded work, several open questions remain. Now that we know the importance of lipid exposure for microglia function, what are the molecular players that mediate this response? Are other cell types in the brain similarly affected, and how is their interaction with microglia regulated by lipids? Building on this work, we seek deeper insights into the mechanisms by which lipid exposure contributes to cellular dysfunction in both neurons and microglia in AD. To complement this broader question, we will ask direct questions inspired by our previous data to explore the roles of two kinds of membrane proteins, CD36 and TMED cargo receptors. Together, these aims will unravel novel molecular and cellular pathways linked to AD progression that may point to new potential therapeutic strategies.