Researchers at the University of Kentucky have a better understanding of the regulation of extracellular vesicles by oxidative stress and how these vesicles spread oxidative stress and may damage neurons. Extracellular vesicles are nanoparticles released by all cell types that help transport information between cells.

The study titled 鈥淐eramide-mediated orchestration of oxidative stress response through filopodia-derived small extracellular vesicles鈥 was recently published in the , the top-tier journal for research on extracellular vesicles.

鈥淭his study lays the groundwork to learn what鈥檚 happening during the exchange of extracellular vesicles between different cell types to then work toward understand the significance of these processes in neurodegenerative diseases like Alzheimer鈥檚 disease,鈥 said Erhard Bieberich, PhD, a professor in the Department of Physiology in the 好色先生 College of Medicine.

Bieberich is the principal investigator on a series of grants from the of the and the that funded the study.

Bieberich鈥檚 research team focused on oxidative stress 鈥 an excess of oxygen radicals in the body. This excess results in damage to cells and tissues. Other studies have shown this plays a role in many chronic and degenerative conditions.

Researchers studied , which are so-called 鈥渋mmortal鈥 cells for their unique ability to continuously grow and divide in the lab. When exposed to hydrogen peroxide, the cells formed filopodia (finger-like projections of cell membranes) and secreted extracellular vesicles (tiny structures released from cell membranes).

鈥淚n our study, we investigated the function of ceramide, which is a type of fatty compound, in filopodia formation and extracellular vesicle secretion, both of which are induced by oxidative stress,鈥 said Bieberich.  

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

鈥淧revious research focused on oxidative stress caused by the accumulation of amyloid in plaques or other proteins in neurons,鈥 said Bieberich. 鈥淲e discovered a novel mechanism by which oxidative stress can be spread through extracellular vesicles, which may propagate cell death even if neurons themselves are not directly exposed to harmful proteins such as amyloid.鈥

The two researchers said the induction of cell death was found particularly in neuronal cells, but plan to further study the process in different types of cells.

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

This research was made possible by the collaboration with two lipid biologists, Stefanka Spassieva, PhD, and Mariana Nikolova-Karakashian, PhD, in the Department of Physiology. They are also co-authors on the publication.

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 represent the official views of the National Institutes of Health.