Systemic Treatment With Liver X Receptor Agonists Raises Apolipoprotein E, Cholesterol, And Amyloid-Beta Peptides In The Cerebral Spinal Fluid Of Rats

Background: Apolipoprotein E (apoE) is a major cholesterol transport protein found in association with brain amyloid from Alzheimer's disease (AD) patients and the epsilon 4 allele of apoE is a genetic risk factor for AD. Previous studies have shown that apoE forms a stable complex with amyloid beta (A beta) peptides in vitro and that the state of apoE lipidation influences the fate of brain A beta, i.e., lipid poor apoE promotes A beta aggregation/deposition while fully lipidated apoE favors A beta degradation/clearance. In the brain, apoE levels and apoE lipidation are regulated by the liver X receptors (LXRs).Results: We investigated the hypothesis that increased apoE levels and lipidation induced by LXR agonists facilitates A beta efflux from the brain to the cerebral spinal fluid (CSF). We also examined if the brain expression of major apoE receptors potentially involved in apoE-mediated A beta clearance was altered by LXR agonists. ApoE, cholesterol, A beta 40, and A beta 42 levels were all significantly elevated in the CSF of rats after only 3 days of treatment with LXR agonists. A significant reduction in soluble brain Ab40 levels was also detected after 6 days of LXR agonist treatment.Conclusions: Our novel findings suggest that central A beta lowering caused by LXR agonists appears to involve an apoE/cholesterol-mediated transport of A beta to the CSF and that differences between the apoE isoforms in mediating this clearance pathway may explain why individuals carrying one or two copies of APOE epsilon 4 have increased risk for AD.