Regulation of neuroinflammation by astrocyte-derived cholesterol.
Neurodegeneration and its concomitant loss of cognitive function are closely linked to neuroinflammation and lipid accumulation, particularly cholesterol. In the brain, astrocytes synthesize cholesterol and deliver it to surrounding cells via apolipoprotein E (apoE). Astrocyte activation increases apoE secretion and promotes neuronal cell death, yet the link between astrocyte-derived cholesterol and inflammation remains unclear. Here we show that pro-inflammatory cytokines stimulate cholesterol synthesis and release from astrocytes. Immune cells take up this cholesterol, which clusters pro-inflammatory receptors in lipid rafts, amplifying inflammatory signaling and gene expression. Astrocyte-specific knockout of cholesterol synthesis (via SREBP2 deletion) reduces inflammatory cytokine production in an Alzheimers disease (AD) mouse model and shortens neuroinflammation triggered by peripheral lipopolysaccharide (LPS) injection. These findings identify astrocyte-derived cholesterol as a paracrine signal that helps drive neuroinflammation in microglia and brain-resident macrophages.