Journal
JOURNAL OF PHARMACY AND PHARMACOLOGY
Volume 63, Issue 8, Pages 1111-1118Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.2042-7158.2011.01309.x
Keywords
Alzheimer's disease; beta amyloid; clearance; P-glycoprotein; up-regulation
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Funding
- National Center For Research Resources [P20RR016456]
- COBRE from the National Institutes of Health [NIH P20-RR021945]
- NORC from the National Institutes of Health [NIH 1P30DK072476]
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Objectives Several studies have suggested the efflux transporter P-glycoprotein (P-gp) to play a role in the etiology of Alzheimer's disease through the clearance of amyloid beta (A beta) from the brain. In this study, we aimed to investigate the possibility of P-gp as a potential therapeutic target for Alzheimer's disease by examining the impact of P-gp up-regulation on the clearance of A beta, a neuropathological hallmark of Alzheimer's disease. Methods Uptake studies for (125)I-radiolabelled A beta(1-40), and fluorescent immunostaining technique for P-gp and fluorescent imaging of A beta(1-40) were carried out in LS-180 cells following treatment with drugs known to induce P-gp expression. Key findings Approximately 10-35% decrease in (125)I-A beta(1-40) intracellular accumulation was observed in cells treated with rifampicin, dexamethasone, caffeine, verapamil, hyperforin, beta-estradiol and pentylenetetrazole compared with control. Also, fluorescent micrographs showed an inverse relationship between levels of P-gp expression and 5-carboxyfluorescein labelled A beta (FAM-A beta(1-40)) intracellular accumulation. Quantitative analysis of the micrographs revealed that the results were consistent with those of the uptake studies using (125)I-A beta(1-40). Conclusions The investigated drugs were able to improve the efflux of A beta(1-40) from the cells via P-gp up-regulation compared with control. Our results elucidate the importance of targeting A beta clearance via P-gp up-regulation, which will be effective in slowing or halting the progression of Alzheimer's disease.
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