A primary-of-its-kind study led by the University of California, Irvine has revealed a recent perpetrator in brain hemorrhages that doesn’t involve blood vessel damage, as previously thought. Scientists have discovered that interactions between senescent red blood cells and capillaries within the brain can result in cerebral microbleeds, providing deeper insight into their formation and identifying potential recent therapeutic targets for treatment and prevention.

The outcomes, recently published online within the journal Journal of Neuroinflammationdescribe how the team was in a position to observe the strategy of red blood cells being retained within the brain’s capillaries after which watch as hemorrhage occurred. Cerebral microbleeds have been related to a wide range of conditions which can be more common in older people, including hypertension, Alzheimer’s disease, and ischemic stroke.

We have now previously investigated this issue in cell culture systems, but our current study has vital implications for expanding our knowledge of the mechanism of cerebral microbleed development. Our findings could have profound clinical implications as we now have identified a link between red blood cell damage and cerebral hemorrhages occurring on the capillary level.”

Dr. Mark Fisher, corresponding creator, professor of neurology at UCI School of Medicine

The team exposed red blood cells to a chemical called tert-butyl hydroperoxide, which caused oxidative stress; the cells were then labeled with a fluorescent tag and injected into mice. Using two different methods, the researchers observed that red blood cells became stuck within the brain’s capillaries and were then removed by a process called endothelial erythrophagocytosis. After emerging from the capillaries, the inflammatory microglial cells engulfed the red blood cells, resulting in the formation of a cerebral hemorrhage.

“It has at all times been assumed that for a cerebral hemorrhage to occur, blood vessels should be damaged or ruptured. We found that increased interactions of red blood cells with brain capillaries provide an alternate source of development,” said co-author Xiangmin Xu, professor of anatomy and neurobiology at UCI and director of the Center for Neural Circuit Mapping on campus. “We want to research intimately the regulation of cerebral capillary clearance and likewise analyze how this process could also be related to insufficient blood supply and ischemic stroke, which is essentially the most common type of stroke, to assist develop targeted therapies.”

Leveraging the broad, collaborative infrastructure and robust resources of the Neural Circuit Mapping Center, other team members included Rachita Sumbria, co-first creator/corresponding creator and associate professor at Chapman University School of Pharmacy; Hai Zhang, co-first creator and postdoctoral researcher in UCI’s Department of Anatomy and Neurobiology; Rudy Chang, co-first creator and graduate of Chapman University School of Pharmacy; Jiahong Sun, postdoctoral researcher at Chapman University; David Cribbs, resident professor on the UCI Institute for Memory Impairment and Neurological Disorders; and Todd Holmes, professor of physiology and biophysics at UCI.

This work was supported by the National Institute on Aging under award numbers R01AG062840, R01AG072896, R35127102, RF1 AG065675, and R01NS121246 and by National Institute of Neurological Disorders and Stroke grant R01NS20989.