Kulas, J. A. | bioRxiv Science

bioRxiv2022

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.

neuroscience↗

bioRxiv2020

Regulation of amyloid processing in neurons by astrocyte-derived cholesterol

Alzheimers Disease (AD) is characterized by the presence of {beta}-Amyloid (A{beta}) plaques, tau tangles, inflammation, and loss of cognitive function. Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic marker for sporadic AD. In vitro evidence suggests apoE links to A{beta} production through nanoscale lipid compartments (also called lipid rafts), but its regulation in vivo is unclear. Here we use super-resolution imaging in mouse brain to show apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) into lipid rafts where it interacts with {beta}- and {gamma}-secretases to generate A{beta}-peptide. We find that targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid and tau burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid rafts where it interacts with -secretase and gives rise to soluble APP (sAPP), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on -, {beta}-, and {gamma}-secretase trafficking, suggesting the ratio of A{beta} to sAPP is regulated by the trafficking of the substrate, not the enzymes. Treatment of astrocytes with inflammatory cytokines IL-1{beta}, IL-6 and TNF- upregulates the synthesis of cholesterol in the astrocytes. We conclude that cholesterol is kept low in neurons to inhibit A{beta} formation and enable astrocyte regulation of A{beta} formation by cholesterol regulation. HighlightsApoE regulates amyloid precursor protein localization to rafts and its exposure to -vs. {beta}-secretase. -, {beta}-, and {gamma}-Secretases are activated by substrate presentation. ApoE specifically transports astrocyte cholesterol to neurons. Astrocyte cholesterol synthesis disruption prevents Alzheimers-associated amyloid pathology in mice.

neuroscience↗