Impact of P-glycoprotein substrates on transendothelial transport of amyloid-β peptide in an in vitro model
Abstract
Alzheimer's disease (AD) is a pervasive neurodegenerative disorder and the leading cause of dementia, strongly associated with amyloid β-peptide (Aβ) accumulation in the cerebrum. In most cases, this aggregation is primarily due to inefficiencies in the degradation and clearance of Aβ, notably its transport across the blood-brain barrier (BBB) into the bloodstream. This study investigates the role of P-glycoprotein (P-gp), a key transporter in transporting Aβ across endothelial-cell monolayers, focusing on the effects of other P-gp substrates on this process. In vitro models of the endothelial vessel wall were tested in monoculture and non-contact coculture techniques, optimizing conditions to enhance barrier integrity, as assessed by transendothelial electrical resistance (TEER) and dextran leakage assays. The hCMEC/D3 cell line was compared to primary human brain microvascular endothelial cells (HBMEC); the latter exhibited greater barrier integrity. Conditions of cell density and days in culture were optimized. The transport of fluorescently labeled Aβ1-40 was tested in the presence of P-gp substrates digoxin, lansoprazole, atorvastatin, and mirabegron. Atorvastatin, digoxin, and lansoprazole significantly increased Aβ efflux, while mirabegron inhibited it, effects qualitatively consistent with the risk for AD associated with their administration to human patients. These findings demonstrate the potential of P-gp substrates to differentially impact Aβ transport, providing…
Read the paper
Related studies
- The Prediction of the In Vitro Release Curves for PLGA-Based Drug Delivery Systems with Neural Networks
- Promising Ursolic Acid as a Novel Antituberculosis Agent: Current Progress and Challenges
- Proof of principle concept for the analysis and functional prediction of rare genetic variants in the CYP2C19 and CYP2D6 genes
- Fabrication, characterization, and docking studies of furosemide-loaded nanosponges using the emulsion solvent diffusion method
- The Effect of Concomitant Administration of Proton Pump Inhibitors on the Pharmacokinetics of CDK4/6 Inhibitors in Rats: Implications for the Evaluation of Hepatic and Transporter-Mediated Drug–Drug Interactions
- Mining the Metabolic Capacity of Clostridium sporogenes Aided by Machine Learning
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.