Transport of Alzheimer's associated amyloid-β catalyzed by P-glycoprotein.
P-glycoprotein (P-gp) is a critical membrane transporter in the blood brain barrier (BBB) and is implicated in Alzheimer's disease (AD). However, previous studies on the ability of P-gp to directly transport the Alzheimer's associated amyloid-β (Aβ) protein have produced contradictory resu...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0250371&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832595714681602048 |
|---|---|
| author | James W McCormick Lauren McCormick Gang Chen Pia D Vogel John G Wise |
| author_facet | James W McCormick Lauren McCormick Gang Chen Pia D Vogel John G Wise |
| author_sort | James W McCormick |
| collection | DOAJ |
| description | P-glycoprotein (P-gp) is a critical membrane transporter in the blood brain barrier (BBB) and is implicated in Alzheimer's disease (AD). However, previous studies on the ability of P-gp to directly transport the Alzheimer's associated amyloid-β (Aβ) protein have produced contradictory results. Here we use molecular dynamics (MD) simulations, transport substrate accumulation studies in cell culture, and biochemical activity assays to show that P-gp actively transports Aβ. We observed transport of Aβ40 and Aβ42 monomers by P-gp in explicit MD simulations of a putative catalytic cycle. In in vitro assays with P-gp overexpressing cells, we observed enhanced accumulation of fluorescently labeled Aβ42 in the presence of Tariquidar, a potent P-gp inhibitor. We also showed that Aβ42 stimulated the ATP hydrolysis activity of isolated P-gp in nanodiscs. Our findings expand the substrate profile of P-gp, and suggest that P-gp may contribute to the onset and progression of AD. |
| format | Article |
| id | doaj-art-d65591ac78d74ab7b49b37ad26f7cea9 |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-d65591ac78d74ab7b49b37ad26f7cea92025-01-18T05:31:08ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-01164e025037110.1371/journal.pone.0250371Transport of Alzheimer's associated amyloid-β catalyzed by P-glycoprotein.James W McCormickLauren McCormickGang ChenPia D VogelJohn G WiseP-glycoprotein (P-gp) is a critical membrane transporter in the blood brain barrier (BBB) and is implicated in Alzheimer's disease (AD). However, previous studies on the ability of P-gp to directly transport the Alzheimer's associated amyloid-β (Aβ) protein have produced contradictory results. Here we use molecular dynamics (MD) simulations, transport substrate accumulation studies in cell culture, and biochemical activity assays to show that P-gp actively transports Aβ. We observed transport of Aβ40 and Aβ42 monomers by P-gp in explicit MD simulations of a putative catalytic cycle. In in vitro assays with P-gp overexpressing cells, we observed enhanced accumulation of fluorescently labeled Aβ42 in the presence of Tariquidar, a potent P-gp inhibitor. We also showed that Aβ42 stimulated the ATP hydrolysis activity of isolated P-gp in nanodiscs. Our findings expand the substrate profile of P-gp, and suggest that P-gp may contribute to the onset and progression of AD.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0250371&type=printable |
| spellingShingle | James W McCormick Lauren McCormick Gang Chen Pia D Vogel John G Wise Transport of Alzheimer's associated amyloid-β catalyzed by P-glycoprotein. PLoS ONE |
| title | Transport of Alzheimer's associated amyloid-β catalyzed by P-glycoprotein. |
| title_full | Transport of Alzheimer's associated amyloid-β catalyzed by P-glycoprotein. |
| title_fullStr | Transport of Alzheimer's associated amyloid-β catalyzed by P-glycoprotein. |
| title_full_unstemmed | Transport of Alzheimer's associated amyloid-β catalyzed by P-glycoprotein. |
| title_short | Transport of Alzheimer's associated amyloid-β catalyzed by P-glycoprotein. |
| title_sort | transport of alzheimer s associated amyloid β catalyzed by p glycoprotein |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0250371&type=printable |
| work_keys_str_mv | AT jameswmccormick transportofalzheimersassociatedamyloidbcatalyzedbypglycoprotein AT laurenmccormick transportofalzheimersassociatedamyloidbcatalyzedbypglycoprotein AT gangchen transportofalzheimersassociatedamyloidbcatalyzedbypglycoprotein AT piadvogel transportofalzheimersassociatedamyloidbcatalyzedbypglycoprotein AT johngwise transportofalzheimersassociatedamyloidbcatalyzedbypglycoprotein |