Crossing the blood-brain barrier to treat Alzheimer’s

Drugs intended to break apart the tangled plaques that cloud the brains of Alzheimer’s patients confront a biological obstacle: the blood-brain barrier. Tightly packed cells along this border between the brain and the bloodstream allow only small molecules to cross, effectively protecting the brain against pathogens, but stifling many treatment strategies.

But recently, a clever approach conceived by Penn researchers has successfully delivered a specially designed protein across the barrier, dissolving plaques in the brains of mice with Alzheimer’s and in the brain tissue of humans who died of the disease. The technique opens the door to a variety of therapies that target maladies that affect the brain and the eyes, which are shielded by a similar physiological blockade—the retinal-blood barrier.

Henry Daniell

Henry Daniell, a professor in the School of Dental Medicine.

Henry Daniell, a professor in the School of Dental Medicine, wondered whether a drug might penetrate the blood-brain barrier if it was attached to one of the small molecules that has the ability to pass through. Along with colleagues, he attached one such molecule, cholera toxin B (CTB), to a molecule called myelin basic protein (MBP), which has been shown to degrade the amyloid beta plaques that are associated with Alzheimer’s disease.

“Small molecules can get across, but can only provide transient relief in improving memory,” says Daniell. “None of the small molecules has been shown to clear the plaques, but MBP can.”

To deliver the fused CTB-MBP protein, the researchers genetically engineered lettuce plants to express the compound—a method that Daniell has used to produce a variety of other drugs and vaccines. They fed capsules of the freeze-dried lettuce plants to mice that had been bred to have Alzheimer’s, and then looked for signs of the disease by staining the brain tissue with a marker that attaches to the amyloid beta plaques.

The researchers discovered that the plaques were reduced by up to 70 percent in the hippocampus and 40 percent in the cortex compared with mice who ate normal lettuce-containing capsules, or no capsules at all—evidence that their drug had crossed the blood-brain barrier.

Though the Penn team doesn’t yet have approval from the Food and Drug Administration to test their approach in living people, they did apply the CTB-MBP protein to the brain tissue of people who died of Alzheimer’s, and found their approach reduced levels of the plaques in a dose-dependent manner in the inferior parietal cortex, a region of the brain believed to play an important role in the development of Alzheimer’s symptoms.

To move these promising results forward, Daniell hopes to partner with Alzheimer’s experts in the Perelman School of Medicine.

“Penn has a great Alzheimer’s research group, so I would like to work with them to see if our approach can truly improve memory in these mice, and eventually in people,” Daniell says.

Originally published on December 12, 2013