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Effect of LXR/RXR agonism on brain and CSF A?40 levels in rats.

ABSTRACT: Alzheimer's disease (AD) is characterized pathologically by the presence of amyloid plaques and neurofibrillary tangles. The amyloid hypothesis contends that the abnormal accumulation of A?, the principal component of amyloid plaques, plays an essential role in initiating the disease. Impaired clearance of soluble A? from the brain, a process facilitated by apolipoprotein E (APOE), is believed to be a contributing factor in plaque formation. APOE expression is transcriptionally regulated through the action of a family of nuclear receptors including the peroxisome proliferator-activated receptor gamma and liver X receptors (LXRs) in coordination with retinoid X receptors (RXRs). It has been previously reported that various agonists of this receptor family can influence brain A? levels in rodents. In this study we investigated the effects of LXR/RXR agonism on brain and cerebrospinal fluid (CSF) levels of A?40 in naïve rats. Treatment of rats for 3 days or 7 days with the LXR agonist, T0901317 or the RXR agonist, bexarotene did not result in significant changes in brain or CSF A?40 levels.

SUBMITTER: Wang S

PROVIDER: S-EPMC4866632 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Effect of LXR/RXR agonism on brain and CSF Aβ40 levels in rats.

Wang Songli S Wen Paul P Wood Stephen S

F1000Research 20160204

Alzheimer's disease (AD) is characterized pathologically by the presence of amyloid plaques and neurofibrillary tangles. The amyloid hypothesis contends that the abnormal accumulation of Aβ, the principal component of amyloid plaques, plays an essential role in initiating the disease. Impaired clearance of soluble Aβ from the brain, a process facilitated by apolipoprotein E (APOE), is believed to be a contributing factor in plaque formation. APOE expression is transcriptionally regulated through ...[more]

PMID: 27239272

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Project description:Cerebrospinal fluid (CSF) and brain tissue sodium levels increase during migraine. However, little is known regarding the underlying mechanisms of sodium homeostasis disturbance in the brain during the onset and propagation of migraine. Exploring the cause of sodium dysregulation in the brain is important, since correction of the altered sodium homeostasis could potentially treat migraine. Under the hypothesis that disturbances in sodium transport mechanisms at the blood-CSF barrier (BCSFB) and/or the blood-brain barrier (BBB) are the underlying cause of the elevated CSF and brain tissue sodium levels during migraines, we developed a mechanistic, differential equation model of a rat's brain to compare the significance of the BCSFB and the BBB in controlling CSF and brain tissue sodium levels. The model includes the ventricular system, subarachnoid space, brain tissue and blood. Sodium transport from blood to CSF across the BCSFB, and from blood to brain tissue across the BBB were modeled by influx permeability coefficients P BCSFB and P BBB , respectively, while sodium movement from CSF into blood across the BCSFB, and from brain tissue to blood across the BBB were modeled by efflux permeability coefficients PBCSFB' and PBBB' , respectively. We then performed a global sensitivity analysis to investigate the sensitivity of the ventricular CSF, subarachnoid CSF and brain tissue sodium concentrations to pathophysiological variations in P BCSFB , P BBB , PBCSFB' and PBBB' . Our results show that the ventricular CSF sodium concentration is highly influenced by perturbations of P BCSFB , and to a much lesser extent by perturbations of PBCSFB' . Brain tissue and subarachnoid CSF sodium concentrations are more sensitive to pathophysiological variations of P BBB and PBBB' than variations of P BCSFB and PBCSFB' within 30 min of the onset of the perturbations. However, P BCSFB is the most sensitive model parameter, followed by P BBB and PBBB' , in controlling brain tissue and subarachnoid CSF sodium levels within 3 h of the perturbation onset.

Project description:Macrophage foam cells store excess cholesterol as cholesteryl esters, which need to be hydrolyzed for cholesterol efflux. We recently reported that silencing expression of carboxylesterase 1 (CES1) in human THP-1 macrophages [CES1KD (THP-1 cells with CES1 expression knocked down) macrophages] reduced cholesterol uptake and decreased expression of CD36 and scavenger receptor-A in cells loaded with acetylated low-density lipoprotein (acLDL). Here, we report that CES1KD macrophages exhibit reduced transcription of cytochrome P45027A1 (CYP27A1) in nonloaded and acLDL-loaded cells. Moreover, levels of CYP27A1 protein and its enzymatic product, 27-hydroxycholesterol, were markedly reduced in CES1KD macrophages. Transcription of LXR? (liver X receptor ?) and ABCA1 (ATP-binding cassette transporter A1) was also decreased in acLDL-loaded CES1KD macrophages, suggesting reduced signaling through PPAR?-CYP27A1-LXR?. Consistent with this, treatment of CES1KD macrophages with agonists for PPAR?, RAR, and/or RAR/RXR partially restored transcription of CYP27A1 and LXR?, and repaired cholesterol influx. Conversely, treatment of control macrophages with antagonists for PPAR? and/or RXR decreased transcription of CYP27A1 and LXR? Pharmacologic inhibition of CES1 in both wild-type THP-1 cells and primary human macrophages also decreased CYP27A1 transcription. CES1 silencing did not affect transcript levels of PPAR? and RXR in acLDL-loaded macrophages, whereas it did reduce the catabolism of the endocannabinoid 2-arachidonoylglycerol. Finally, the gene expression profile of CES1KD macrophages was similar to that of PPAR? knockdown cells following acLDL exposures, further suggesting a mechanistic link between CES1 and PPAR?. These results are consistent with a model in which abrogation of CES1 function attenuates the CYP27A1-LXR?-ABCA1 signaling axis by depleting endogenous ligands for the nuclear receptors PPAR?, RAR, and/or RXR that regulate cholesterol homeostasis.

Dataset Information

Effect of LXR/RXR agonism on brain and CSF A?40 levels in rats.

Publications

Effect of LXR/RXR agonism on brain and CSF Aβ40 levels in rats.

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