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

J Pharm Pharmacol. 2011 Aug;63(8):1111-8. doi: 10.1111/j.2042-7158.2011.01309.x. Epub 2011 Jun 11.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Caffeine / pharmacology
  • Cell Line
  • Central Nervous System Agents / pharmacology*
  • Central Nervous System Agents / therapeutic use
  • Dexamethasone / pharmacology
  • Estradiol / pharmacology
  • Humans
  • Pentylenetetrazole / pharmacology
  • Phloroglucinol / analogs & derivatives
  • Phloroglucinol / pharmacology
  • Rifampin / pharmacology
  • Staining and Labeling
  • Terpenes / pharmacology
  • Up-Regulation
  • Verapamil / pharmacology

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Amyloid beta-Peptides
  • Central Nervous System Agents
  • Terpenes
  • Caffeine
  • Estradiol
  • Dexamethasone
  • Verapamil
  • Phloroglucinol
  • hyperforin
  • Rifampin
  • Pentylenetetrazole