Cholesterol efflux as a critical component of Alzheimer's disease pathogenesis

The risk of Alzheimer's disease and the levels of amyloid deposition are altered by factors associated with high cholesterol levels. When cells have high levels of cholesterol, they induce an efflux system of to maintain a proper cholesterol equilibrium. In the brain, cholesterol is converted to 24S hydroxycholesterol by the enzyme Cyp46. 24S hydroxycholesterol promotes gene transcription through interactions with LXR. We have found that in cells derived from the brain, two proteins important for cholesterol efflux, ABCA1 and apoE, are induced by this system. Furthermore, we have found that pharmacologic induction of LXR also induced secreted Abeta levels, particularly levels of Abeta42. We suggest that the risk of amyloid deposition associated with high cholesterol may be through induction of the LXR system.