Scientists at the University of Virginia have discovered that microglia (the immune cells of the brain’s residents) act as microscopic traffic controllers, thereby regulating blood flow through the tiniest blood vessels that feed neurons.
This discovery could reshape how doctors approach Alzheimer’s disease and other neurodegenerative diseases, where damaged blood flow can damage brain tissue from essential nutrients.
The study, published in Nature Communications, shows that microglia use an enzyme called cyclooxygenase-1 (COX1) to maintain the proper “tongue” in capillaries, the silk filament that makes up the brain’s most extensive blood vessel network. When the researchers eliminated these immune cells in mice, the capillary diameter shrunk significantly and blood flow decreased by about 50%.
The brain’s energy crisis
Our brain is metabolic and, despite weighing only 2% of the body’s total energy consumes 20% of the body. This huge energy requirement requires a complex delivery system: 400 miles of blood vessels in the human brain, branching into countless capillaries, reaching within 8-20 microns of each neuron.
“For some time, microglia have been suggested to play an important role in regulating vascular function,” said Ukpong B. Eyo, senior author and researcher of the study. “Through this study, we provide the clearest evidence that they do regulate blood flow to the brain, specify the location of the function in the small blood vessels or capillaries in the brain, and determine the enzymes they use to do this.”
The research team used complex imaging techniques to track the interaction of individual microglia with capillaries in the brains of living mice. They found that there were about 65% of microglia clusters around the capillaries, while other immune cells called peripheral macrophages were mainly associated with larger blood vessels.
Main research results
The Virginia team’s experiment revealed several key insights:
- Microglia express COX1 at ten times higher levels at the level of support cells in the brain
- Removal of microglia immediately causes capillary contraction and reduces blood flow
- Genetic elimination of COX1 in specific microglia produces the same vascular problems
- Recover microglia to reverse these blood flow defects
Using a technique called 2 ablation, researchers can eliminate individual microglia while observing real-time changes in nearby capillaries. “We observed a significant reduction in capillary diameter after global microglia ablation, which restored to baseline values after microglia regeneration,” the researchers reported.
Alzheimer’s connection
This discovery has special significance for Alzheimer’s disease, where blood flow has long been considered a contributor and consequence of neurodegeneration. Previous studies have shown that COX1 inhibitors produce different results in Alzheimer’s patients, but this study suggests that timing may be crucial.
“The microglia enzymes identified in this study are targeted enzymes for patients with Alzheimer’s disease to date, although the results are mixed,” said William A. Mills III, first author of the study. “Our study shows that these therapeutic agents will receive the greatest benefit if prescribed based on the therapeutic window for microglia in Alzheimer’s disease, which is the focus of our ongoing research.”
This study challenges previous hypotheses about which brain cells control vascular function. Although astrocytes have traditionally been considered as the primary regulator of blood flow, this study localized microglia as an equally important participant, especially in maintaining baseline capillary tone.
Future treatment possibilities
The discovery opens up several potential therapeutic avenues. Treatment can focus on restoring microglia function to improve cerebral blood flow rather than simply targeting disease symptoms. This approach may benefit not only Alzheimer’s patients, but also patients with vascular dementia and some forms of Parkinson’s disease.
“Although microglia are dysfunctional in neurodegenerative diseases, our work now increases the possibility of improving blood flow defects by targeting microglia,” Eyo explained.
The team identified several key questions for future research: whether microglia work independently or coordinate with other brain cells, starting this regulatory effect during development, and whether replacement of dysfunctional microglia can restore healthy blood flow in the diseased brain.
The study, supported by several national institutes of health, represents UVA’s broad commitment to Alzheimer’s research, including the recently established Harrison Family Translational Research Center for Alzheimer’s and Neurodegenerative Diseases.
As researchers continue to map complex networks of cells that maintain brain health, the discovery highlights how immune cells are not only defenders of disease defense, but essential companions to the basic life support system of the brain.
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