New Evidence for P-gp-Mediated Export of Amyloid-β Peptides in Molecular, Blood-Brain Barrier and Neuronal Models

Defective clearance mechanisms lead to the accumulation of amyloid-beta (A beta) peptides in the Alzheimer's brain. Though predominantly generated in neurons, little is known about how these hydrophobic, aggregation-prone, and tightly membrane-associated peptides exit into the extracellular space where they deposit and propagate neurotoxicity. The ability for P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, to export A beta across the blood-brain barrier (BBB) has previously been reported. However, controversies surrounding the P-gp-A beta interaction persist. Here, molecular data affirm that both A beta(40) and A beta(42) peptide isoforms directly interact with and are substrates of P-gp. This was reinforced ex vivo by the inhibition of A beta(42) transport in brain capillaries from P-gp-knockout mice. Moreover, we explored whether P-gp could exert the same role in neurons. Comparison between non-neuronal CHO-APP and human neuroblastoma SK-N-SH cells revealed that P-gp is expressed and active in both cell types. Inhibiting P-gp activity using verapamil and nicardipine impaired A beta(40) and A beta(42) secretion from both cell types, as determined by ELISA. Collectively, these findings implicate P-gp in A beta export from neurons, as well as across the BBB endothelium, and suggest that restoring or enhancing P-gp function could be a viable therapeutic approach for removing excess A beta out of the brain in Alzheimer's disease.

Automated summary

P-glycoprotein (P-gp) has been found to assist in the export of Aβ from neurons and across the blood-brain barrier (BBB) endothelium. Molecular data confirm direct interaction between Aβ(40) and Aβ(42) peptide isoforms with P-gp, suggesting that enhancing P-gp function could be a potential therapeutic approach for Alzheimer's disease.