PROJECT SUMMARY Alzheimer’s disease (AD) and related dementias (ADRD) are multifactorial disorders with complex pathological mechanisms. Proteinopathy, neuronal impairments, and neuroinflammation are well-known hallmarks of ADRD. Lipid dysregulation is also a prominent feature of AD pathology. Genes that control lipid metabolism are implicated in AD, and plasma and brain lipid levels are altered in disease. Therapeutically modifying lipids might alleviate behavioral and cognitive decline and risk of neurodegenerative disease, but additional studies are needed to better understand lipid-related molecular changes and their effects on brain function and disease. Astrocytes are essential for brain lipid homeostasis due to astrocytic enrichment of lipid-related factors and the dependence of neurons on astrocytes for lipid turnover and various lipid-based processes. However, the effects of dementia-associated pathological factors and disease cascades on astrocytic lipids have not been defined. Moreover, how changes in astrocyte lipids are regulated and how they influence forebrain neurons is unclear. Further investigations are required to define astrocytic lipid signatures and lipid-based alterations and how they influence neuronal function and vulnerability to disease. Our preliminary data suggest that proteinopathy and neuroimmune factors influence astrocyte lipid synthesis and release, which may affect astrocytic-neuronal interactions and neuronal health in aging and disease. Based on our novel results, we hypothesize that AD-related proteinopathy and neuroimmune signaling induce maladaptive changes in astrocytic lipid metabolism and release that promote neuronal vulnerability in dementia. In the proposed R21 study, we will use lipidomics and other advanced approaches in mouse models to characterize the spatiotemporal alterations in astrocyte lipids during aging and disease (Aim 1) and investigate how alterations in astrocytic lipids are regulated and may promote neuronal impairments and vulnerability to disease (Aim 2). We will perform innovative lipidomic profiling in astrocytes at different ages and across brain regions, which will address previously underappreciated molecular signatures in astrocytes. We will also use a novel approach of spatial lipidomics to resolve lipid-based changes across brain regions and use isolated mouse astrocytes and human iPSC-derived astrocytes to identify cell-autonomous effects and molecular mechanisms that regulate astrocyte lipids and lipid-based astrocytic-neuronal interactions. In summary, the proposed study seeks to elucidate novel lipid signatures and molecular mechanisms associated with ADRD, which may reveal new therapeutic strategies for neurodegenerative disorders.