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 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. KEY FINDINGS: 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. CONCLUSIONS: 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.
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 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. KEY FINDINGS: 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. CONCLUSIONS: 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.
Authors: Fabian Fernandez; Wade Morishita; Elizabeth Zuniga; James Nguyen; Martina Blank; Robert C Malenka; Craig C Garner Journal: Nat Neurosci Date: 2007-02-25 Impact factor: 24.884
Authors: Alaa H Abuznait; Hisham Qosa; Belnaser A Busnena; Khalid A El Sayed; Amal Kaddoumi Journal: ACS Chem Neurosci Date: 2013-02-25 Impact factor: 4.418
Authors: Alaa H Abuznait; Hisham Qosa; Nicholas D O'Connell; Jessica Akbarian-Tefaghi; Paul W Sylvester; Khalid A El Sayed; Amal Kaddoumi Journal: Food Chem Toxicol Date: 2011-08-10 Impact factor: 6.023