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bioRxiv · 10.1101/2020.06.18.159632

Regulation of amyloid processing in neurons by astrocyte-derived cholesterol

Wang, H.·Kulas, J. A.·Ferris, H.·Hansen, S.
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Abstract

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.

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Wang, H., Kulas, J. A., Ferris, H., Hansen, S.. 2020-06-18. Regulation of amyloid processing in neurons by astrocyte-derived cholesterol. https://doi.org/10.1101/2020.06.18.159632

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