P-glycoprotein removes Alzheimer’s-associated toxin from the brain

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(A) The first framework of the SMU simulation shows amyloid-β bound to P-gp drug binding domains. (B) The final picture of the same simulation shows P-gp pushing an amyloid protein across the cell membrane out of the cell. Credit: Lauren Ammerman

A team of SMU biological scientists has confirmed that P-glycoprotein (P-gp) has the ability to remove a toxin associated with Alzheimer’s disease from the brain.

The finding could lead to new treatments for the disease that affects nearly 6 million Americans. It was this hope that motivated lead researchers James W. McCormick and Lauren Ammerman to continue research as SMU graduate students after they both lost a grandmother due to the disease while they were at SMU.

In the Alzheimer’s brain, abnormal levels of β-amyloid proteins clump together to form plaques that collect between neurons and can alter cell function. This is believed to be one of the key factors that triggers memory loss, confusion, and other common symptoms of Alzheimer’s disease.

“We have been able to demonstrate both computationally and experimentally that P-gp, a critical toxin pump in the body, is capable of transporting this β-amyloid. said John Wise, an associate professor in the Department of Biological Sciences at the SMU and co-author of the study published in PLOS ONE.

“If you could find a way to induce more P-glycoprotein into the protective blood-brain barrier for people susceptible to Alzheimer’s disease, perhaps they could adopt this treatment and help postpone or prevent the onset of the disease.” He said. Wise stressed that the theory needs more research.

The SMU (Southern Methodist University) study also provides strong evidence for the first time that P-gp can pump much larger toxins than previously thought.

P-gp is the natural way to remove toxins from cells. Similar to how a house tank pump removes water from the basement, P-gp swallows harmful drugs or toxins inside the cell and spits them out of the cell.

“Finding P-gp where the body seeks to protect an organ from toxins and the brain is no exception,” explained co-author Pia Vogel, an SMU professor and director of the SMU Drug Discovery, Design, and Delivery Center.

The large size of the Amyloid-β created questions about whether the P-glycoprotein could inhale it and pump it back.

“Amyloid-β is perhaps five times larger than the small, drug-like molecules known to move P-glycoproteins. It would be like taking New York pizza and trying to fill the whole slice in your mouth and swallow it. “Wise said.

The fact that P-gp seems to be able to do just that “greatly expands the possible range of things that P-gp can carry, which opens up the possibility that it may interact with other factors that were previously thought impossible,” said McCormick, a former graduate student in biological sciences at SMU.

The investigation was personal

It is possible that SMU researchers would never have investigated the link between P-gp and amyloid-β proteins had it not been for McCormick’s persevering search for the connection. A doctoral student, who graduated in 2017, had seen preliminary work suggesting that P-gp might play a role in extracting amyloid protein from the brain and asked his medical advisors, Vogel and Wise, if it could take a while to check it out.

Teachers admit they first tried to discourage him because they were more focused on the role of P-gp in creating resistance to chemotherapy in cancer patients. However, McCormick was “passionate” about finding out if P-gp could protect someone from Alzheimer’s, Vogel said.

He spent hours of his own time using a computer-generated P-glycoprotein model that he and Wise created. The model allows researchers to couple almost any drug to the P-gp protein and observe how it would behave in the P-gp “pump”. Vogel, Wise, and other SMU scientists have been studying the protein for years to identify compounds that could reverse the failure of chemotherapy in aggressive cancers.

McCormick completed the computational work with the help of his fiancée, Ammerman, who received his doctorate in biology from SMU in May.

Together, they performed several simulations of the P-gp protein using SMU’s high-performance computer, ManeFrame II, and found that each time, P-gp was able to “swallow” β-amyloid proteins and expel them. of the cells.

“For the scientist of mine, it was absolutely amazing that this bomb could consume something so big,” Vogel said. “Go [Wise] and I did not predict that this would be possible. “

Two in vitro experiments confirmed the computational work

The researchers performed two experiments in the laboratory to confirm the computational results.

In one experiment, Ammerman used laboratory-purchased β-amyloid proteins that had been stained fluorescent green, making them easy to detect under a microscope. In multiple assays, Ammerman exposed human cells to these β-amyloid proteins. He used two types of human cells: one where P-gp was strongly expressed and one where P-gp was not. This allowed him to test the difference between the two and see if P-gp was pumping amyloid-β out.

Amyloid proteins were shown to be expelled from human cells that had P-gp overexpressed in them, supporting the theory that P-gp removes amyloid proteins in contact.

Another in vitro experiment came to the same conclusion from a different direction. Former graduate student Gang (Mike) Chen worked at SMU’s Center for Drug Discovery, Design, and Delivery to demonstrate that an Alzheimer’s-related β-amyloid caused changes in P-use. gp of adenosine triphosphate (ATP), indicating that there was interaction between the two.

ATP hydrolysis produces the energy that P-gp uses to transport toxins or drugs out of the cell. When there are no toxins, the ATP rate of P-gp remains quite low. When challenged with charge transport, the ATP hydrolysis activity of P-gp tends to increase dramatically.

“While our work may not help our grandparents, I hope it can help others in the future,” Ammerman said. “The more we know, the more power we have – and researchers after us – to deal with and address these devastating diseases.”


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More information:
James W. McCormick et al, P-glycoprotein-catalyzed Alzheimer’s-associated amyloid-β transport, PLOS ONE (2021). DOI: 10.1371 / journal.pone.0250371

Citation: P-Glycoprotein Removes Alzheimer’s-Associated Toxin (2021, June 16) Retrieved June 17, 2021 from https://medicalxpress.com/news/2021-06-p-glycoprotein-alzheimer-associated -toxin-brain.html

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