Abstract
Defective clearance mechanisms lead to the accumulation of amyloid-beta (Aβ) 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 Aβ across the blood-brain barrier (BBB) has previously been reported. However, controversies surrounding the P-gp–Aβ interaction persist. Here, molecular data affirm that both Aβ40 and Aβ42 peptide isoforms directly interact with and are substrates of P-gp. This was reinforced ex vivo by the inhibition of Aβ42 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 Aβ40 and Aβ42 secretion from both cell types, as determined by ELISA. Collectively, these findings implicate P-gp in Aβ 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 Aβ out of the brain in Alzheimer’s disease.
Document Type
Article
Publication Date
2021
Digital Object Identifier (DOI)
https://doi.org/10.3390/ijms22010246
Funding Information
This research was funded by a seed grant from the University of Sydney, Australia. A.B.C. and A.Y. were recipients of Australian Government scholarships. A.M.S.H. was supported by grant number 2R01AG039621 from the National Institute on Aging.
Related Content
The data presented in this study are available on request from the corresponding authors.
Repository Citation
Chai, Amanda B.; Hartz, Anika M. S.; Gao, Xuexin; Yang, Alryel; Callaghan, Richard; and Gelissen, Ingrid C., "New Evidence for P-gp-Mediated Export of Amyloid-β PEPTIDES in Molecular, Blood-Brain Barrier and Neuronal Models" (2021). Sanders-Brown Center on Aging Faculty Publications. 154.
https://uknowledge.uky.edu/sbcoa_facpub/154
Notes/Citation Information
Published in International Journal of Molecular Sciences, v. 22, issue 1, 246.
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This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).