British study links nanoparticles to oxidative stress and neuronal death

LEXINGTON, Ky. (July 23, 2024) — Researchers at the University of Kentucky have a better understanding of how oxidative stress regulates extracellular vesicles and how these vesicles can spread oxidative stress and damage neurons. Extracellular vesicles are nanoparticles released by all cell types that help transport information between cells.

The study, titled “Ceramide-mediated orchestrated of oxidative stress response through filopodia-derived small extracellular vesicles,” was recently published in the Journal of Extracellular Vesicles, the most prestigious journal for extracellular vesicle research.

“This study lays the foundation for understanding what happens during the exchange of extracellular vesicles between different cell types and then understanding the importance of these processes in neurodegenerative diseases such as Alzheimer’s disease,” said Erhard Bieberich, Ph.D., professor in the Department of Physiology at the UK College of Medicine.

Bieberich is the principal investigator on a series of grants from the National Institute on Aging (NIA), the National Institutes of Health (NIH), and the U.S. Department of Veterans Affairs that funded the study.

Bieberich’s research team focused on oxidative stress – an excess of oxygen radicals in the body. This excess leads to cell and tissue damage. Other studies have shown that this stress plays a role in many chronic and degenerative diseases.

Researchers studied HeLa cells, so-called “immortal” cells that have the unique ability to grow and divide continuously in the laboratory. When exposed to hydrogen peroxide, the cells formed filopodia (finger-like extensions of cell membranes) and secreted extracellular vesicles (tiny structures released from cell membranes).

“In our study, we investigated the function of ceramide, a type of fatty compound, in filopodia formation and extracellular vesicle secretion, both of which are triggered by oxidative stress,” said Bieberich.

“Using a novel metabolic labeling technique, we found that these two processes are controlled by two enzymes that generate ceramide at the plasma membrane,” said Zainuddin Quadri, first author of the study and senior research associate in the Department of Physiology. “This leads to the release of ceramide-rich small extracellular vesicles from filopodia, which then attack the mitochondria and cause cell death.”

“Previous research has focused on oxidative stress caused by the accumulation of amyloid in plaques or other proteins in neurons,” said Bieberich. “We have discovered a new mechanism by which oxidative stress can be spread through extracellular vesicles, which can lead to cell death even when the neurons themselves are not directly exposed to harmful proteins such as amyloid.”

The two researchers said the induction of cell death was particularly observed in nerve cells, but plan to further study the process in other cell types.

Their findings suggest that targeting the interaction between the two enzymes could be a potential therapeutic target to prevent cell death caused by oxidative stress.

This research was made possible through collaboration with two lipid biologists, Stefanka Spassieva, Ph.D., and Mariana Nikolova-Karakashian, Ph.D., in the Department of Physiology. They are also co-authors of the paper.

The research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under award numbers R01AG064234, RF1AG078338, and R21AG078601. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health.

This material is based on work supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. Government.