New evidence for p-gp-mediated export of amyloid-β peptides in molecular, blood-brain barrier and neuronal models

Amanda B. Chai, Anika M.S. Hartz, Xuexin Gao, Alryel Yang, Richard Callaghan, Ingrid C. Gelissen

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish
Article number246
Pages (from-to)1-20
Number of pages20
JournalInternational Journal of Molecular Sciences
Volume22
Issue number1
DOIs
StatePublished - Jan 1 2021

Bibliographical note

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. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health.

Funding Information:
Funding: 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. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health.

Publisher Copyright:
© 2020 by the authors. Li-censee MDPI, Basel, Switzerland.

Keywords

  • ABCB1
  • Alzheimer’s disease
  • Amyloid-beta
  • Neuron
  • P-glycoprotein
  • SK-N-SH

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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