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.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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: Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
authors: Alaa H
authors: AH
authors: Abuznait
authors: Courtney
authors: C
authors: Cain
authors: Drury
authors: D
authors: Ingram
authors: David
authors: D
authors: Burk
authors: Amal
authors: A
authors: Kaddoumi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology; D002460:Cell Line; D002491:Central Nervous System Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003907:Dexamethasone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D010433:Pentylenetetrazole / Q000494:pharmacology; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D013194:Staining and Labeling; D013729:Terpenes / Q000494:pharmacology; D015854:Up-Regulation; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D002491:Central Nervous System Agents; D013729:Terpenes; D002110:Caffeine; D004958:Estradiol; D003907:Dexamethasone; D014700:Verapamil; D010696:Phloroglucinol; C001654:hyperforin; D012293:Rifampin; D010433:Pentylenetetrazole