Protecting the brain from toxins, pathogens, and random molecules that don’t belong there is the job of the blood-brain barrier. But the same tightly woven cell network that blocks toxic substances also blocks the entry of potentially life-saving medicines. “The blood-brain barrier is your best friend when you are healthy,” says Anne Eichmann, Ensign Professor of Medicine, “but an adversary if you have a brain disease.”
Eichmann’s team has now developed a chemical tool that can open that barrier in mice. The discoveries began with experiments by Kevin Boyé, a postdoctoral associate in Eichmann’s lab. When he removed a receptor called Unc5B from embryonic mice, the mice died. Without Unc5B, the thin membrane that lines the heart and blood vessels failed, and the blood vessel network couldn’t form properly. Also, a protein called Claudin5, important for keeping tight junctions between the blood-brain barrier’s cells, was significantly reduced.
Next, the team discovered that Unc5B controls another function (the Wnt signaling pathway) essential to keeping the barrier intact. Then Boyé removed Unc5B from adult mice whose blood-brain barriers had already developed. The barriers remained open. He also found that removing the substance Netrin-1—which activates the Unc5B receptor—produced a defect in the barrier.
With all this information, Eichmann says, “we thought we should be able to make an injectable antibody that could block Netrin-1” temporarily. It worked. Using fluorescent dyes that let them see inside the brain, the team saw that injecting the antibody into the bloodstreams of healthy mice opened their blood-brain barriers for a short time. (The results are in Nature Communications.)
Many questions remain to be answered, Eichmann cautions. But the team may have found a path that could eventually deliver needed medications directly to the human brain—perhaps, she says, “to treat conditions as diverse as Alzheimer’s disease and brain cancers.”
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