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Researchers identify new cause of brain bleeding immediately after stroke

Stroke is not only a complex and devastating neurological condition; it’s the fourth-leading cause of death and primary reason for disability in the United States. It results in severe blood-brain barrier damage, which allows entry of blood-borne material into the brain, contributing to cellular death and permanent cognitive and movement impairments.

Researchers in the lab of Axel Nimmerjahn, collaborating with Dritan Agalliu, an assistant professor of developmental and cell biology at UC Irvine, have discovered a new mechanism that allows blood to enter the brain immediately after stroke, revealing a possible means to create new therapies that may reduce or prevent stroke-induced damage in the brain. In their research, Nimmerjahn and Agalliu developed a novel transgenic mouse strain in which they used a fluorescent tag to see the barrier-forming tight junctions between the cells that make up the blood vessels in the nervous system. This allowed them to image dynamic changes in the barrier during and after stroke in living animals.

The microscope image on the left shows brain blood vessels (red) with intact junctions (yellow lines) between cells that compose the vessel walls. The image on the right shows blood vessels and junctions two days after a stroke. Blood material has entered the brain (dark red background). Scientists from the Salk Institute and UC Irvine showed that early blood material leakage (within 6 hours after stroke) is due to increased carrier protein transport through the cells of the vessel walls and not through gaps at the junctions, as previously thought.

While seeing that the barrier function was rapidly impaired after stroke (within six hours), they unexpectedly found that this early barrier failure is not due to the breakdown of tight junctions between the blood vessel cells, as had previously been suspected, because tight junction breakdown did not occur until two days after the injury. Instead, they reported dramatic increases in carrier proteins, called serum albumin, flowing directly into brain tissue. These proteins travel through the cells that make up the blood vessels, called endothelial cells, using a specialized transport system that normally operates only in non-brain vessels or immature vessels within the central nervous system (CNS). This finding suggests that the transport system underlies the initial failure of the barrier, allowing entry of blood material into the brain within six hours of a stroke.

Early regulation of the specialized transport system in the CNS following stroke may spur development of imaging methods or biomarkers in human studies to identify the initial stages of stroke and thereby prevent damage as early as possible.

Plus, says Nimmerjahn, “Our new transgenic mouse strain and imaging approaches may also allow mechanistic insight into other CNS disorders associated with blood-brain barrier dysfunction, such as brain infection, amyotrophic lateral sclerosis or vascular cognitive impairment.” His laboratory is currently developing and applying new light microscopic tools to uncover how CNS immune cells respond to injury, mediate repair and influence nervous system function and behavior.

Results of the stroke study appeared in Neuron.