Regulation Of Beta-Amyloid Production In Neurons By Cholesterol

Alzheimer's disease (AD) is characterized by the presence of amyloid beta (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 risk factor for sporadic AD. In vitro evidence suggests that apoE links to A beta production through nanoscale lipid compartments (lipid clusters), but its regulation in vivo is unclear. Here, we use superresolution imaging in the mouse brain to show that apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) in and out of lipid clusters, where it interacts with beta-and gamma-secretases to generate A beta-peptide. We find that the 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 clusters, where it interacts with alpha-secretase and gives rise to soluble APP-alpha (sAPP-alpha), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on alpha-, beta-, and gamma-secretase trafficking, suggesting that the ratio of A beta to sAPP-alpha is regulated by the trafficking of the substrate, not the enzymes. We conclude that cholesterol is kept low in neurons, which inhibits A beta accumulation and enables the astrocyte regulation of A beta accumulation by cholesterol signaling.