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Disturbances in cerebral cholesterol metabolism have been implicated in the pathogenesis of Alzheimer's disease (AD). Here, we provide evidence that alterations in brain cholesterol homeostasis also can be a consequence of disease progression. We found that APPSLxPS1mut mice, at the age of 9 months when AD-like pathology starts to develop, display increased levels of the cholesterol precursor desmosterol and of the cholesterol metabolite 27-hydroxy(OH)cholesterol in their cerebellum in comparison with wild-type controls. At the age of 21 months, when APPSLxPS1mut brain contains abundant amyloid deposits, desmosterol levels had further increased (>200% in comparison with wild-type mice) in all brain regions examined. 24(S)-OHcholesterol levels were increased in hippocampus and cerebellum of the APPSLxPS1mut mice, while 27-OHcholesterol levels were increased in cerebellum exclusively. Brain cholesterol levels remained unaffected. In line with the fact that desmosterol and 24(S)-OHcholesterol are Liver X Receptor (LXR) activators, the LXR-target genes Abca1 and Apoc1 were upregulated predominantly in hippocampus of APPSLxPS1mut mice at both ages evaluated. The reduced expression of the enzyme that converts desmosterol into cholesterol, the Selective AD indicator 1 gene (Seladin-1/Dhcr24), in both cortex and cerebellum may underlie the increased desmosterol levels in 21 month-old APPSLxPS1mut mice.

Background and Aims The disposition and sterol-lowering effect of ezetimibe are associated with long-lasting enterosystemic circulation, which is initiated by secretion of ezetimibe and its glucuronide via intestinal P-glycoprotein (P-gp) (ABCB1) and the multidrug resistance-associated protein 2 (MRP2) (ABCC2) into gut lumen. Hepatic uptake and secretion may contribute to recycling. To obtain deeper insight into the intestinal and hepatic processes, the disposition of ezetimibe was studied in the presence of rifampin (INN, rifampicin), a modulator of P-gp, MRP2, and hepatic organic anion (uptake) transporting polypeptides (OATPs) (SLCOs). Methods The disposition of ezetimibe (20 mg orally) alone and after coadministration of rifampin (600 mg orally) was measured in a crossover study of 8 healthy subjects with the SLCO1B1 *1a/*1a genotype. Concentrations of ezetimibe and its glucuronide in serum, urine, and feces, as well as cholesterol, lathosterol, and the plant sterols campesterol and sitosterol in serum, were quantified by use of liquid chromatography and gas chromatography with mass spectrometric detection. Results After rifampin administration, the maximum serum concentrations of ezetimibe and its glucuronide were significantly elevated (12.0 ± 4.20 ng/mL versus 4.67 ± 2.72 ng/mL, P = .017, and 282 ± 73.8 ng/mL versus 107 ± 35.3 ng/mL, P = .012, respectively). The area under the curve of ezetimibe was not affected (102 ± 37.6 ng · h/mL versus 140 ± 86.3 ng · h/mL, P = not significant), whereas that of the glucuronide was markedly increased (2150 ± 687 ng · h/mL versus 1030 ± 373 ng · h/mL, P = .012). Renal clearance remained unchanged. Fecal excretion of ezetimibe was markedly decreased (7.6 ± 2.2 mg versus 10.4 ± 1.8 mg, P = .036), whereas renal excretion of the glucuronide was strongly elevated (4.8 ± 1.9 mg versus 2.0 ± 1.2 mg, P = .049) after coadministration. The onset of a significant sterol-lowering effect of ezetimibe was significantly shortened by rifampin coadministration. Conclusions Coadministration of rifampin increases the maximum serum concentrations of ezetimibe but reduces its enterosystemic recycling, most likely by inhibition of the secretion of ezetimibe and its glucuronide via P-gp and MRP2. Clinical Pharmacology & Therapeutics (2006) 80, 477–485; doi: 10.1016/j.clpt.2006.07.006