Regulation of amyloid processing in neurons by astrocyte-derived cholesterol

Alzheimers Disease (AD), a common and burdensome neurodegenerative disorder, is characterized by the presence of {beta}-Amyloid (A{beta}) plaques, inflammation, and loss of cognitive function. A cholesterol-dependent process sorts A{beta}-producing enzymes into nanoscale lipid compartments (also called lipid rafts). Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic marker for sporadic AD. Evidence suggests apoE links to A{beta} production through lipid rafts, but so far there has been little scientific validation of this link in vivo. Here we use super-resolution imaging to show apoE utilizes astrocyte-derived cholesterol to specifically traffic 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 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 a signaling molecule kept low in neurons to inhibit raft function, decrease A{beta} formation, and enable astrocyte regulation of APP by cholesterol control of substrate presentation.