Article

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

Department of Neurosymptomatic Disorders, Merck Research Laboratories, West Point, PA 19486, USA. .
Molecular Neurodegeneration (Impact Factor: 5.29). 10/2010; 5:44. DOI: 10.1186/1750-1326-5-44
Source: PubMed

ABSTRACT Apolipoprotein E (apoE) is a major cholesterol transport protein found in association with brain amyloid from Alzheimer's disease (AD) patients and the ε4 allele of apoE is a genetic risk factor for AD. Previous studies have shown that apoE forms a stable complex with amyloid β (Aβ) peptides in vitro and that the state of apoE lipidation influences the fate of brain Aβ, i.e., lipid poor apoE promotes Aβ aggregation/deposition while fully lipidated apoE favors Aβ degradation/clearance. In the brain, apoE levels and apoE lipidation are regulated by the liver X receptors (LXRs).
We investigated the hypothesis that increased apoE levels and lipidation induced by LXR agonists facilitates Aβ 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 Aβ clearance was altered by LXR agonists. ApoE, cholesterol, Aβ40, and Aβ42 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 Aβ40 levels was also detected after 6 days of LXR agonist treatment.
Our novel findings suggest that central Aβ lowering caused by LXR agonists appears to involve an apoE/cholesterol-mediated transport of Aβ 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 ε4 have increased risk for AD.

0 Followers
 · 
233 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Liver X receptors (LXRs) have been of interest as targets for the treatment of atherosclerosis for over a decade. In recent years, LXR modulators have also garnered interest for potential use in the treatment of inflammation, Alzheimer's disease (AD), dermatological conditions, hepatic steatosis and oncology. To date, no LXR modulator has successfully progressed beyond phase I clinical trials. In this review, we summarize published medicinal chemistry efforts in the context of the available crystallographic data, druglikeness and isoform selectivity. In addition, we discuss the challenges to be overcome before an LXR modulator can reach clinical use.
    Journal of Medicinal Chemistry 05/2014; 57(17). DOI:10.1021/jm500442z · 5.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The pathogenesis of Alzheimer’s disease (AD) has been mostly linked to aberrant amyloid beta (Aβ) and tau proteins metabolism, disturbed lipid/cholesterol homeostasis, and progressive neuroinflammation. Liver X receptors (LXR) are ligand-activated transcription factors, best known as the key regulators of cholesterol metabolism and transport. In addition, LXR signaling has been shown to have significant anti-inflammatory properties. In this brief review, we focus on the outcome of studies implicating LXR in the pathogenesis, modulation, and therapy of AD.
    09/2013; 4(3):349-356. DOI:10.2478/s13380-013-0136-z
  • [Show abstract] [Hide abstract]
    ABSTRACT: Passive amyloid-β (Aβ) vaccination has shown significant effects on amyloid pathology in pre-depositing amyloid-β protein precursor (AβPP) mice but the results in older mice are inconsistent. A therapeutic effect of LXR and RXR agonists consisting of improved memory deficits and Aβ pathology has been demonstrated in different Alzheimer's disease (AD) mouse models. Here, we report the effect of a combination of N-terminal Aβ antibody and synthetic LXR agonist T0901317 (T0) on AD-like phenotype of APP23 mice. To examine the therapeutic potential of this combination the treatment of mice started at 11 months of age, when amyloid phenotype in this model is fully developed, and continued for 50 days. We show that Aβ immunization with or without LXR agonist restored the performance of APP23 transgenic mice in two behavior paradigms without affecting the existing amyloid plaques. Importantly, we did not observe an increase of brain microhemorrhage which is considered a significant side effect of Aβ vaccination. Target engagement was confirmed by increased Abca1 and ApoE protein level as well as increased ApoE lipidation in soluble brain extract. In interstitial fluid obtained by microdialysis, we demonstrate that immunization and T0 significantly reduced Aβ levels, indicating an increased Aβ clearance. We found no interaction between the immunotherapy and T0, suggesting no synergism, at least with these doses. The results of our study demonstrate that anti-Aβ treatments can ameliorate cognitive deficits in AβPP mice with advanced AD-like phenotype in conjunction with a decrease of Aβ in brain interstitium and increase of ApoE lipidation without affecting the existing amyloid plaques.
    Journal of Alzheimer's disease: JAD 03/2014; 41(2). DOI:10.3233/JAD-132789 · 3.61 Impact Factor

Full-text (4 Sources)

Download
29 Downloads
Available from
May 30, 2014