Penn Vet study plugs ‘leaky’ blood-brain barrier in mice with MS-like disease

Many neurological diseases impair the blood-brain barrier, a highly regulated blockade that, when functioning normally, keeps all but select molecules from traveling from the circulatory system into the brain. In individuals with multiple sclerosis (MS), for example, this barrier springs leaks that lead to inflammation and neuronal damage.

New research by Jorge Ivan Alvarez of Penn’s School of Veterinary Medicine, working together with colleagues from the University of Montreal and McGill University, has keyed in on a protein called netrin-1 that upholds the barrier function. In experiments with mice with a disease similar to MS, treatment with netrin-1 lessened their symptoms.

Alvarez, an assistant professor in Penn Vet’s Department of Pathobiology, has for many years studied the blood-brain barrier. In earlier work as a postdoctoral researcher at Montreal, he found that a protein called sonic hedgehog helped maintain the barrier by preventing immune cells from entering the brain.

In their current work, experiments using human brain cells in culture suggested that netrin-1 expression seemed to be reliant on sonic hedgehog, so Alvarez and his colleagues shifted their attention.

“Netrins are best known to play a role in guiding the direction of axon growth, as well as morphogenesis and tissue formation,” Alvarez says. “But our work suggested a new role for netrin-1 in the blood-brain barrier.”

Because people with MS have “leaky” blood-brain barriers, the researchers looked at barrier cells from people who had died from the disease. The team found that disease lesions in these individuals had higher levels of netrin-1 compared to the healthy lesions—implying that perhaps the diseased cells boosted netrin-1 expression in an attempt to tighten the blood-brain barrier and keep damaging inflammatory cells out of the brain.

In further experiments, Alvarez and colleagues found that netrin-1 significantly reduced the movement of molecules across cultures of human blood-brain barrier endothelial cells by upregulating proteins that control the barrier function. Mice lacking netrin-1 had a build-up of molecules in their brains that are normally only found in the blood.

MS is known to affect the blood-brain barrier and involves damaging inflammation in the brain. To see if they could protect the brain from this inflammation, the researchers tried administering netrin-1 to mice with a disease very similar to MS.

“We found the disease outcome is better when the mice were treated with netrin-1, even when delivered after the disease process had begun,” Alvarez says.

With further study into sonic hedgehog, netrin-1, and other molecules involved in maintaining the blood-brain barrier, Alvarez and his colleagues hope to make headway at a possible treatment for MS.