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- Title
Up-regulation of P-glycoprotein reduces intracellular accumulation of beta amyloid: investigation of P-glycoprotein as a novel therapeutic target for Alzheimer's disease.
- Authors
Abuznait, Alaa H.; Cain, Courtney; Ingram, Drury; Burk, David; Kaddoumi, Amal
- Abstract
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 β) 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 β, a neuropathological hallmark of Alzheimer's disease. Methods Uptake studies for 125I-radiolabelled A β1-40, and fluorescent immunostaining technique for P-gp and fluorescent imaging of A β1-40 were carried out in LS-180 cells following treatment with drugs known to induce P-gp expression. Key findings Approximately 10-35% decrease in 125I-A β1-40 intracellular accumulation was observed in cells treated with rifampicin, dexamethasone, caffeine, verapamil, hyperforin, β-estradiol and pentylenetetrazole compared with control. Also, fluorescent micrographs showed an inverse relationship between levels of P-gp expression and 5-carboxyfluorescein labelled A β (FAM-A β1-40) intracellular accumulation. Quantitative analysis of the micrographs revealed that the results were consistent with those of the uptake studies using 125I-A β1-40. Conclusions The investigated drugs were able to improve the efflux of A β1-40 from the cells via P-gp up-regulation compared with control. Our results elucidate the importance of targeting A β clearance via P-gp up-regulation, which will be effective in slowing or halting the progression of Alzheimer's disease.
- Subjects
P-glycoprotein; ALZHEIMER'S disease; AMYLOID beta-protein; ETIOLOGY of diseases; CELLS
- Publication
Journal of Pharmacy & Pharmacology, 2011, Vol 63, Issue 8, p1111
- ISSN
0022-3573
- Publication type
Article
- DOI
10.1111/j.2042-7158.2011.01309.x