Up-regulation of P-glycoprotein reduces intracellular accumulation of beta amyloid: investigation of P-glycoprotein as a novel therapeutic target for Alzheimer's disease.

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. Uptake studies for ¹²⁵I-radiolabelled Aβ₁₋₄₀, and fluorescent immunostaining technique for P-gp and fluorescent imaging of Aβ₁₋₄₀ were carried out in LS-180 cells following treatment with drugs known to induce P-gp expression. Approximately 10-35% decrease in ¹²⁵I-Aβ₁₋₄₀ 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-Aβ₁₋₄₀) intracellular accumulation. Quantitative analysis of the micrographs revealed that the results were consistent with those of the uptake studies using ¹²⁵I-Aβ₁₋₄₀. The investigated drugs were able to improve the efflux of Aβ₁₋₄₀ 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.