Astrocyte Lipid Metabolism: From Physiological Homeostasis to Reactive Phenotype Plasticity in Neurodegeneration.

Abstract

Astrocytes are one of the most abundant types of glial cells in the central nervous system (CNS) and play pivotal roles in metabolic support, synaptic regulation, and neurotransmitter homeostasis. Astrocytic dysfunction is closely associated with the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD), and lipid metabolism constitutes a central axis for maintaining astrocyte function and CNS homeostasis. Here, we provide a systematic review of recent advances in astrocyte lipid metabolism, summarizing the fundamental roles of astrocytes in the CNS and focusing on the biosynthesis, degradation, and trafficking mechanisms of fatty acids, cholesterol, and the tightly linked organelles known as lipid droplets. We further analyze the relationships and potential pathogenic mechanisms linking lipid metabolic disturbances, such as impaired fatty acid β-oxidation, cholesterol accumulation, and dysregulated lipid droplet dynamics, to neurodegeneration. The review also presents current frameworks for classifying reactive astrocytes, including the classical A1/A2 paradigm and more recently identified subtypes, and examines how lipid metabolic processes influence phenotype transitions. Finally, we propose a regulatory axis: lipid metabolism dysregulation leads to cellular phenotype conversion, which in turn drives disease progression, to emphasize the central role of lipid metabolism in astrocyte reactivity and neuropathology. This synthesis fills a gap in the literature at the interface of lipid metabolism and astrocyte functional regulation, and it offers a conceptual framework and candidate targets to guide future investigation into metabolic mechanisms of neurodegeneration and the development of precision therapeutic strategies.