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: 6.56). 10/2010; 5(1):44. DOI: 10.1186/1750-1326-5-44
Source: PubMed


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.

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Available from: John J Renger, Oct 09, 2015
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    • "APOE is a protein that is intimately involved in all of these processes [16]: the expression of the APOE4 allele leads to a propensity for increased Aβ aggregation in sporadic AD [17] and increased risk of Aβ deposition in capillaries [13]. APOE plays a direct role in Aβ efflux across the blood brain barrier to circulating plasma [18], [19], and its overexpression promotes Aβ proteolysis via enzymes such as neprilysin and insulin degrading enzyme [20]. Overexpression of neprilysin and insulin degrading enzyme decrease Aβ levels in transgenic amyloid precursor protein (APP) mouse models and improve cognition [21]. "
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    ABSTRACT: The structural integrity of cerebral vessels is compromised during ageing. Abnormal amyloid (Aβ) deposition in the vasculature can accelerate age-related pathologies. The cerebrovascular response associated with ageing and microvascular Aβ deposition was defined using quantitative label-free shotgun proteomic analysis. Over 650 proteins were quantified in vessel-enriched fractions from the brains of 3 and 9 month-old wild-type (WT) and Tg-SwDI mice. Sixty-five proteins were significantly increased in older WT animals and included several basement membrane proteins (nidogen-1, basement membrane-specific heparan sulfate proteoglycan core protein, laminin subunit gamma-1 precursor and collagen alpha-2(IV) chain preproprotein). Twenty-four proteins were increased and twenty-one decreased in older Tg-SwDI mice. Of these, increases in Apolipoprotein E (APOE) and high temperature requirement serine protease-1 (HTRA1) and decreases in spliceosome and RNA-binding proteins were the most prominent. Only six shared proteins were altered in both 9-month old WT and Tg-SwDI animals. The age-related proteomic response in the cerebrovasculature was distinctly different in the presence of microvascular Aβ deposition. Proteins found differentially expressed within the WT and Tg-SwDI animals give greater insight to the mechanisms behind age-related cerebrovascular dysfunction and pathologies and may provide novel therapeutic targets.
    PLoS ONE 02/2014; 9(2):e89970. DOI:10.1371/journal.pone.0089970 · 3.23 Impact Factor
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    • "In addition, Eckert et al. (2007) demonstrated that TO90-mediated induction of ABCA1, ABCG1 and apoE was accompanied by the decrease of cholesterol levels in cortical synaptosomal plasma membranes [53]. Furthermore, administration of TO90 to rats upregulated apoE and total cholesterol levels in cerebrospinal fluid (CSF), suggesting that LXR activation stimulates elimination of brain cholesterol via secretion of apoE-lipidated particles into the CSF [54]. "
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    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
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