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 (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 125 I‐radiolabelled A β 1–40 , and fluorescent immunostaining technique for P‐gp and fluorescent imaging of A β 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 β 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 A β (FAM‐A β 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 β 1–40 . Conclusions  The investigated drugs were able to improve the efflux of A β 1–40 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.