From astrocyte cholesterol synthesis to synaptic dysfunction: mechanisms of neuron-glia lipid coupling

The brain contains a large proportion of the body's cholesterol, highlighting its importance in central nervous system function. Cholesterol supports neuronal membrane structure, synapse formation, synaptic vesicle activity, receptor signaling, and myelin integrity. Because the blood-brain barrier limits the entry of peripheral lipoproteins, the brain relies mainly on local cholesterol synthesis, transport, recycling, and turnover.

This review examines the mechanisms that regulate astrocyte-to-neuron cholesterol transfer and explains how defects in SREBP-dependent synthesis, ApoE lipidation, ABC transporter-mediated export, neuronal uptake, intracellular trafficking, and cholesterol turnover contribute to synaptic dysfunction and neurodegeneration.

In the adult brain, astrocytes are an important source of cholesterol for neurons. Astrocytic cholesterol synthesis is regulated by sterol regulatory element-binding proteins, which control the expression of key cholesterol-biosynthetic genes. Astrocytes release cholesterol in ApoE-containing lipoprotein particles through ATP-binding cassette transporters. Neurons acquire astrocyte-derived cholesterol through LDLR/LRP1, redistribute it via NPC1/NPC2, and eliminate excess cholesterol as 24 S-hydroxycholesterol through CYP46A1.

Disruption of this pathway impairs membrane organization, lipid raft signaling, synaptic function, and neuronal survival. These disturbances are associated with Alzheimer's disease, Huntington's disease, and multiple sclerosis.