The release of cholesterol from choroid plexus epithelial cells (CPE) plays an important role in cholesterol homeostasis in the CSF. The purpose of this study was to clarify the molecules involved in cholesterol release in CPE and the regulation mechanisms of the cholesterol release by the liver X receptor (LXR) using a conditionally immortalized CPE line (TR-CSFB3). The mRNA expression of LXRa, LXRb and their target genes, ATP-binding cassette transporter (ABC)A1, ABCG1, ABCG4 and ABCG5, were detected in rat choroid plexus. ABCA1 and ABCG1 protein were detected in the plasma membrane of TR-CSFB3 cells. Following treatment with 24S-hydroxycholesterol, an endogenous LXR ligand, the expression of ABCA1 and ABCG1 were induced in TR-CSFB3 cells. Moreover, apolipoprotein (apo)AI-and high-density lipoprotein (HDL)-mediated cholesterol release to the apical side of TR-CSFB3 cells was facilitated by this treatment, whereas that to the basal side was not affected. Following 24S-hydroxycholesterol treatment, apoE3-dependent cholesterol release from TR-CSFB3 cells was enhanced more than the apoE4-dependent release. These results suggest that LXR activation facilitates cholesterol release into the CSF from CPE through the functional induction of ABCA1 and ABCG1. The difference between apoE3 and apoE4 suggests that the cholesterol release from CPE is related to the development of neurodegenerative diseases.

Amyloid-b peptide (Ab) concentration in CSF is potentially a diagnostic and therapeutic target for Alzheimer's disease (AD). The purpose of this study was to clarify the elimination mechanism of human Ab(1-40) human receptor-associated protein (RAP) and the elimination was attenuated in either anti-low-density lipoprotein receptorrelated protein (LRP)1 antibody-treated or RAP-deficient mice, suggesting that a member(s) of the low-density lipoprotein receptor gene family is involved in the elimination of hAb(1-40) from CSF. The amounts of LRP1 and LRP2 proteins were determined by means of liquid chromatographytandem mass spectrometry, and the LRP1 content in rat choroid plexus was determined to be 3.7 fmol/lg protein, whereas the LRP2 content was below the detection limit (< 0.2 fmol/lg protein). Conditionally, immortalized rat choroid plexus epithelial cells exhibited predominant apical-to-basal and apical-to-cell transport of [ 125 I]hAb(1-40). These results indicated that hAb(1-40) is actively eliminated from CSF and this process is at least partly mediated by LRP1 expressed at choroid plexus epithelial cells, which therefore play a role in determining CSF concentrations of hAb(1-40). Keywords: Alzheimer's disease, amyloid-b peptide, bloodcerebrospinal fluid barrier, choroid plexus, conditionally immortalized rat choroid plexus epithelial cell line cells, lowdensity lipoprotein receptor-related protein-1.

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A highly sensitive and reliable analytical method that uses liquid chromatography/electrospray ionization tandem mass spectrometry coupled with a simple on-line solid-phase extraction was developed to monitor occupational exposure by measuring cyclophosphamide in the urine of medical staffs who handle this anticancer drug. The quantitation limit is 3 pg/mL with a signal-to-noise ratio of more than 10, and the measurement range is 3 pg/mL to 3 ng/mL. Using this method, trace levels of cyclophosphamide have been detected in the urine of two pharmacists after handling this anticancer drug during more than 4 years exposure survey. This finding strongly suggests that it is very important to monitor the occupational exposure of medical staffs who handle anticancer drugs in order to assess the health hazard and control the use of these chemotherapies. These data also show that this analytical method can be successfully used to monitor occupational exposure by measuring the levels of residual cyclophosphamide in human urine.