Background:
Apolipoprotein E (apoE) is a major cholesterol transport protein found in association with brain amyloid from Alzheimer's disease (AD) patients and the e4 allele of apoE is a genetic risk factor for AD. Previous studies have shown that apoE forms a stable complex with amyloid-beta (Abeta) peptides in vitro and that the state of apoE lipidation influences the fate of brain Abeta, i.e., lipid poor apoE promotes Abeta aggregation/ deposition while fully lipidated apoE favors Abeta 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 Abeta 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 Abeta clearance was altered by LXR agonists. ApoE, cholesterol, Abeta40, and Abeta42 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 Abeta40 levels was also detected after 6 days of LXR agonist treatment.
Conclusions:
Our novel findings suggest that central Abeta lowering caused by LXR agonists appears to involve apoE/cholesterol-mediated efflux of Abeta 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 apoE4 have increased risk for AD.
Read the original article at Molecular Neurodegeneration.
Systemic treatment with liver X receptor agonists raises apolipoprotein E, cholesterol, and amyloid-beta peptides in the cerebral spinal fluid of rats
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