TY - JOUR
T1 - Systemic treatment with liver X receptor agonists raises apolipoprotein E, cholesterol, and amyloid-β peptides in the cerebral spinal fluid of rats
AU - Suon, Sokreine
AU - Zhao, Jie
AU - Villarreal, Stephanie A.
AU - Anumula, Nikesh
AU - Liu, Mali
AU - Carangia, Linda M.
AU - Renger, John J.
AU - Zerbinatti, Celina V.
N1 - Funding Information:
Charles Crapo, PhD, Brian Himelbloom, PhD, and Robert Pfutzenreuter are affiliated with the University of Alaska, Fishery Industrial Technology Center, 118 Trident Way, Kodiak, AK 99615. Chong Lee, PhD, Professor, is affiliated with the University of Rhode Island, Food Science and Nutrition Research Center, 530 Liberty Lane, West Kingston, RI 02892. This research was supported by the National Marine Fisheries Service Saltonstall-Kennedy Program, NOAA Award No. NA46FDO354.
PY - 2010
Y1 - 2010
N2 - Background. Apolipoprotein E (apoE) is a major cholesterol transport protein found in association with brain amyloid from Alzheimer's disease (AD) patients and the 4 allele of apoE is a genetic risk factor for AD. Previous studies have shown that apoE forms a stable complex with amyloid (A) peptides in vitro and that the state of apoE lipidation influences the fate of brain A, i.e., lipid poor apoE promotes A aggregation/deposition while fully lipidated apoE favors A 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 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 clearance was altered by LXR agonists. ApoE, cholesterol, A40, and A42 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 A40 levels was also detected after 6 days of LXR agonist treatment. Conclusions. Our novel findings suggest that central A lowering caused by LXR agonists appears to involve an apoE/cholesterol-mediated transport of A 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 4 have increased risk for AD.
AB - Background. Apolipoprotein E (apoE) is a major cholesterol transport protein found in association with brain amyloid from Alzheimer's disease (AD) patients and the 4 allele of apoE is a genetic risk factor for AD. Previous studies have shown that apoE forms a stable complex with amyloid (A) peptides in vitro and that the state of apoE lipidation influences the fate of brain A, i.e., lipid poor apoE promotes A aggregation/deposition while fully lipidated apoE favors A 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 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 clearance was altered by LXR agonists. ApoE, cholesterol, A40, and A42 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 A40 levels was also detected after 6 days of LXR agonist treatment. Conclusions. Our novel findings suggest that central A lowering caused by LXR agonists appears to involve an apoE/cholesterol-mediated transport of A 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 4 have increased risk for AD.
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U2 - 10.1186/1750-1326-5-44
DO - 10.1186/1750-1326-5-44
M3 - Article
AN - SCOPUS:77958516916
VL - 5
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
SN - 1750-1326
IS - 1
M1 - 44
ER -