Systemic treatment with liver X receptor agonists raises apolipoprotein E, cholesterol, and amyloid-β peptides in the cerebral spinal fluid of rats

Sokreine Suon, Jie Zhao, Stephanie A. Villarreal, Nikesh Anumula, Mali Liu, Linda M. Carangia, John J. Renger, Celina V. Zerbinatti

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number44
JournalMolecular Neurodegeneration
Volume5
Issue number1
DOIs
StatePublished - 2010
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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