Looking under the hood: a new method to examine the brain following injury
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While medical research continues to provide new and improved ways to examine the inner workings of our body, the brain remains a difficult organ to study. To look under the hood of our most complex organ, researchers need to find creative ways to bypass the highly complex defence mechanisms separating our brains from external threats. These defence mechanisms make it extremely difficult to monitor the brain following an insult such as the blocking or rupturing of a blood vessel, leading to a stroke.
Excitingly, researchers at the University of Western Ontario used a novel non-invasive method to examine brain inflammation post stroke. This neuroinflammation could be harmful to the brain, resulting in worse neurological outcomes such as neurodegeneration, if it goes unchecked. Hence, researchers were interested in monitoring microglia, the resident immune cell of the brain. These cells activate and take on a pro-inflammatory state following a brain injury, which is beneficial in the acute stage for cleaning the damaged brain region. However, the pro-inflammatory state can be detrimental if it remains chronically activated.
Currently, observing microglia activity within the brain has been limited due to an inability to obtain microglia samples without damaging the brain, or the lack of advanced imaging techniques that can target that cell type. Thus, to study microglia in a non-invasive way, researchers aimed to take advantage of small particles called extracellular vesicles.
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Extracellular vesicles, or EVs for short, are small particles released by all our cells, and are made up of an outer lipid shell and an inner cargo (refer to the image above for a visual diagram of an EV). This cargo can be composed of different proteins, lipids, and nucleic acid, and functions as a way for cells to communicate with each other. In essence, EVs play the role of an envelope carrying messages between cells across the body.
Interestingly, EVs from all different cell types could be found circulating in our blood and have the natural capability of bypassing the brain’s defence mechanisms. Therefore, EVs released from microglia could be found circulating in the blood, and isolating those EVs has the potential to provide researchers with a snapshot of the neuroinflammatory profile of the brain.
In this study, the researchers first began by validating whether microglia activation could be detected using microglia-derived EVs. To do so, microglia grown in a dish were exposed to specific molecules that resulted in their activation, leading to a pro-inflammatory state. EVs isolated from these activated microglia showed increased levels of specific protein markers in comparison to non-activated microglia. These specific protein markers sit on the surface of the EV (similar to what is seen in the image of the EV above) and could help identify the EV to have originated from active microglia. Consequently, these markers can now enable researchers to detect increases in microglia activation, which could indicate an increase in neuroinflammation, and the potential ability to monitor brain injury.
Next, the researchers sought to measure alterations in microglia-derived EVs following a stroke. Towards that goal, they used a rat stroke model and extracted plasma (i.e., the liquid portion of the blood, extracted from a blood sample) following a stroke. Using this plasma, EVs derived from activated microglia were isolated by employing the specific protein markers they uncovered earlier. In comparison to plasma derived from rats who did not have a stroke, the plasma in the rat stroke model had a significant increase of EVs derived from activated microglia. This increase is expected, as it reflects the known increase of microglia activation and neuroinflammation following a stroke.
Overall, this study presents an exciting and novel avenue for examining the brain following injury. Using blood to inspect the state of the brain, the non-invasive nature of this method could make it an attractive option for many patients and health care professionals. While this research is still in its early stages, these findings bring us a step closer to better examining our most precious engine, our brain.
Original Article:
Roseborough, A. D., Myers, S. J., Khazaee, R., Zhu, Y., Zhao, L., Iorio, E., Elahi, F. M., Pasternak, S. H., & Whitehead, S. N. (2023). Plasma derived extracellular vesicle biomarkers of microglia activation in an experimental stroke model. Journal of Neuroinflammation, 20(1), 20. https://doi.org/10.1186/s12974-023-02708-x
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