December 9, 2023

As the body’s control center, your brain needs a strong security against circulating pathogens or toxins. The blood-brain barrier (BBB) ​​performs this important function, but it can become “leaky”. Now, Stanford scientists have identified therapeutic molecules that could help patch it up, potentially preventing the neurological disorder.

The BBB forms a semipermeable lining inside the blood vessels that supply the brain, serving as the brain’s bodyguard, keeping out nearly everything but nutrients, ions, and molecules that are critical to neurological function. Unfortunately, if this barrier is compromised, it can lead to a range of neurological diseases such as multiple sclerosis, Alzheimer’s or brain cancer.

“A leaky blood-brain barrier is a common pathway for many brain diseases, so being able to seal the barrier has been a long-sought goal in medicine,” said Calvin Kuo, senior author of the study.

For the new study, the Stanford scientists looked at molecules that might allow them to do just that. The key appears to be a communication pathway called WNT signaling, which has been found to help maintain the BBB. The pathway is initiated by a protein receptor called “frizzled.”

The team identified a molecule that activates FZD4, the Frizzled receptor in blood vessel endothelial cells in the brain. They then developed a version of this molecule, called L6-F4-2, that binds to the receptor and triggers WNT signaling 100-fold more efficiently.

To test it, the researchers gave their L6-F4-2 molecule to mice with a genetic mutation that causes a similar barrier to become leaky — a barrier that protects the retina. Sure enough, the team found that blood vessels in the treated mice became denser and less leaky than before. In a similar experiment, the therapy strengthened the blood-brain barrier around the cerebellum of mice with a similar genetic defect.

In another test, the researchers investigated the molecule’s effect on stroke, which disrupts the blood-brain barrier and allows potentially harmful substances to enter the brain. They found that giving mice L6-F4-2 reduced the severity of strokes, improved their survival and helped repair leaks in blood vessels.

Of course, as with any animal research, there’s no guarantee these results will necessarily apply to humans, but the team says it could be a first step toward treating and preventing neurological disorders.

“We hope this will be the first step in developing a new generation of drugs capable of repairing the blood-brain barrier, using very different strategies and molecular targets than current drugs,” Kuo said.

The study was published in the journal natural communication.

source: Stanford University