PT  - JOURNAL ARTICLE
AU  - Hao Wang
AU  - Joshua A. Kulas
AU  - Heather A. Ferris
AU  - Scott B. Hansen
TI  - Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol
AID  - 10.1101/2020.06.18.159632
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.18.159632
4099  - http://biorxiv.org/content/early/2020/10/14/2020.06.18.159632.short
4100  - http://biorxiv.org/content/early/2020/10/14/2020.06.18.159632.full
AB  - Alzheimer’s Disease (AD) is characterized by the presence of β-Amyloid (Aβ) 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 Aβ 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 β- and γ-secretases to generate Aβ-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 α-secretase and gives rise to soluble APPα (sAPPα), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and γ-secretase trafficking, suggesting the ratio of Aβ to sAPPα is regulated by the trafficking of the substrate, not the enzymes. Treatment of astrocytes with inflammatory cytokines IL-1β, IL-6 and TNF-α upregulates the synthesis of cholesterol in the astrocytes. We conclude that cholesterol is kept low in neurons to inhibit Aβ formation and enable astrocyte regulation of Aβ formation by cholesterol regulation.Highlights ApoE regulates amyloid precursor protein localization to rafts and its exposure to α-vs. β-secretase.α-, β-, and γ-Secretases are activated by substrate presentation.ApoE specifically transports astrocyte cholesterol to neurons.Astrocyte cholesterol synthesis disruption prevents Alzheimer’s-associated amyloid pathology in mice.Competing Interest StatementThe authors have declared no competing interest.