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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:Organotins, a chemical family with over 30 congeners to which humans are directly exposed to through food consumption, are a chemical class widely used as stabilizers in polyvinyl chloride, and biocides in antifouling products. Aside from tributyltin (TBT), toxicological information on other organotin congeners, such as triphenyltin (TPT), remains scarce. Our previous work has demonstrated that TBT can interfere with cholesterol trafficking in steroidogenic cells. Given their structural similarities, we hypothesized that TPT, similar to TBT, disrupts intracellular cholesterol transport and impairs steroidogenesis in ovarian theca cells. To test this, human and ovine primary ovarian theca cells were isolated, purified and exposed to TPT at environmentally relevant doses (1 or 10 ng/ml) in pre-luteinized (48 h exposure) or luteinizing cells (72 h exposure). Intracellular cholesterol levels, progesterone, and testosterone secretion and gene expression of nuclear receptors, cholesterol transporters, and steroidogenic enzymes were evaluated. In ovine cells, TPT upregulated StAR, ABCA1, and SREBF1 mRNA and ABCA1 protein in both pre-luteinized and luteinized stages. TPT did not alter intracellular cholesterol or testosterone synthesis, but upregulated progesterone production. Inhibitor and shRNA knockdown approaches were then used to evaluate the role of retinoid X receptor (RXR) and liver X receptor (LXR) on TPT's effects. TPT upregulated ABCA1 and StAR expression was blocked by both LXR and RXR antagonists. TPT's effect on ABCA1 expression was reduced in LXRβ and RXRβ knockdown theca cells. Similar findings were obtained with primary human theca cells. No synergistic effect of TBT and TPT was observed. In conclusion, at an environmentally relevant dose, TPT upregulates theca cell cholesterol transporter ABCA1 expression via RXR and LXR pathways. Similar effects of TPT on human and sheep theca cells supports its conserved mechanism across mammalian theca cells.

Dataset Information

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

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

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