The Brain’s Border Patrol – Blood Brain Barrier

The blood brain barrier (BBB) forms a tight security gateway between blood vessels and brain tissue. Blood flow throughout the brain is crucial to deliver the oxygen and nutrients required for the brain to function properly. Even though the brain comprises only about 2% of body mass, it is responsible for nearly a quarter of the body’s oxygen consumption. Blood flow is so crucial to the brain that when blood flow stops, brain functions halt within seconds. At the same time the brain also requires a very specific environment in order to function properly. Miniscule changes in pH, chemical concentrations, and protein composition around brain cells can have drastic and detrimental effects to cellular signaling and thus, brain function. The BBB acts as the border control to the brain, selectively allowing the necessary molecules to pass through while denying entry to everything else flowing through the blood vessels.

The BBB plays an important role in brain diseases. A tightly closed BBB prevents drugs from crossing into the brain to treat diseases. And, breakdown of this barrier has been implicated in a wide variety of neurodegenerative diseases including epilepsy, multiple sclerosis, Parkinson’s, and Alzheimer’s. Furthermore, an opening of the BBB following stroke and brain trauma appears to exacerbate damage and lead to worsened outcomes. Therefore, scientists are increasingly interested in learning how to manipulate the barrier: temporarily opening the BBB to deliver drugs to the brain, and closing it to prevent damage from diseases.

The mechanisms of BBB opening and closing are not yet fully understood. The barrier is made up of so-called tight junctions between the endothelial cells lining the blood vessels. These tight junctions are formed by a series of proteins on the outside of the cells that interlock with each other, much like a zipper, creating a seal between cells. On the brain tissue side of the BBB, astrocytes, neurons, and pericytes are able to modulate the tightness of the seal in response to a variety of conditions. BBB opening appears to play a beneficial role following disease and trauma. It may help in clearing cellular debris remaining from extensive cell death, as well as the damaging proteins that aggregate in Alzheimer’s and Huntington’s. But, in a variety of neurodegenerative disorders, a loss of tight junction proteins causes the BBB to become leaky, which has been associated with a worsening of symptoms. In some neurodegenerative disorders such as stroke and multiple sclerosis, it appears that BBB opening also allows immune cells from the rest of the body into the brain, and these cells exacerbate the damage by attacking healthy cells. As with many complex responses to damage in the brain, it seems likely that a small opening is helpful, but a prolonged, chronic opening is detrimental.

Due to its complexity, research on the BBB is technically difficult. However, scientists are beginning to understand the complex role this structure plays and how its opening and closing may be manipulated. There are a number of therapies currently in development that utilize this greater understanding of the BBB. Therapies targeting the BBB present an exciting opportunity to develop novel and unique therapies to treat brain disorders by temporarily opening a closed BBB to deliver drugs to the brain and closing an open BBB to prevent further damage.

References

Neuwelt, E., Bauer, B., Fahlke, C., Fricker, G., Iadecola, C., Janigro, D., Leybaert, L., Molnár, Z., O’Donnell, M., Povlishock, J., Saunders, N., Sharp, F., Stanimirovic, D., Watts, R., & Drewes, L. (2011). Engaging neuroscience to advance translational research in brain barrier biology Nature Reviews Neuroscience, 12 (3), 169-182 DOI: 10.1038/nrn2995

Zlokovic, B. (2011). Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders Nature Reviews Neuroscience DOI: 10.1038/nrn3114

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