Up-regulation of P-glycoprotein reduces intracellular accumulation of beta amyloid: Investigation of P-glycoprotein as a novel therapeutic target for Alzheimer's disease
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 (Aβ) 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 Aβ, a neuropathological hallmark of Alzheimer's disease. Methods: Uptake studies for 125I-radiolabelled Aβ 1-40, and fluorescent immunostaining technique for P-gp and fluorescent imaging of Aβ 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 125I-Aβ 1-40 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 Aβ (FAM-Aβ 1-40) intracellular accumulation. Quantitative analysis of the micrographs revealed that the results were consistent with those of the uptake studies using 125I-Aβ 1-40. Conclusions: The investigated drugs were able to improve the efflux of Aβ 1-40 from the cells via P-gp up-regulation compared with control. Our results elucidate the importance of targeting Aβ clearance via P-gp up-regulation, which will be effective in slowing or halting the progression of Alzheimer's disease. © 2011 The Authors JPP © 2011 Royal Pharmaceutical Society.
Publication Source (Journal or Book title)
Journal of Pharmacy and Pharmacology
Abuznait, A., Cain, C., Ingram, D., Burk, D., & Kaddoumi, A. (2011). Up-regulation of P-glycoprotein reduces intracellular accumulation of beta amyloid: Investigation of P-glycoprotein as a novel therapeutic target for Alzheimer's disease. Journal of Pharmacy and Pharmacology, 63 (8), 1111-1118. https://doi.org/10.1111/j.2042-7158.2011.01309.x