Many drugs aiming to treat Alzheimer’s disease, including some in clinical trials, have failed because they couldn't breach the brain’s natural defenses.
Now, researchers at the University of Pennsylvania (Penn) say they’ve found a way to move proteins through this blood-brain barrier to break up plaques in brain tissue associated with Alzheimer’s.
The Blood-Brain Barrier and Alzheimer’s Plaques
The blood-brain barrier protects the brain from outside substances, such as viruses and harmful chemicals. While critical for survival, this cellular lining around the brain and spinal cord creates a problem for delivering drugs to treat neurological disorders like Alzheimer’s.
Alzheimer's plaques are formed by clumps of beta-amyloid proteins. When these bundles accumulate in the brain, the plaques can block crucial signaling between nerve cells.
While most common therapies for Alzheimer’s disease only manage symptoms, this new research provides insight into the possibility of using oral drugs to break up and dissolve the plaques themselves.
Navigating the Blood-Brain Barrier
The Penn researchers recently published a study in the journal Molecular Therapy outlining a technique to cross difficult barriers in the body, including the blood-brain barrier and the retinal-blood barrier in the eye.
Henry Daniell, a professor at Penn's School of Dental Medicine's departments of biochemistry and pathology and director of translational research, first proposed the concept of a “molecular crossing guard,” created by attaching a drug molecule to a carrier capable of passing through the blood-brain barrier. They chose to use the protein cholera toxin B, a non-toxic carrier approved by the U.S. Food and Drug Administration.
They paired the carrier with myelin basic protein, which has been showed to degrade amyloid plaques in Alzheimer’s patients. They then added a green fluorescent protein to the mix and fed young mice the freeze-dried compound in pill form. It turns out that the crossing-guard theory works.
“When we found the glowing protein in the brain and the retina we were quite thrilled,” Daniell said in a statement. “If the protein could cross the barrier in healthy mice, we thought it was likely that it could cross in Alzheimer's patients' brains, because their barrier is somewhat impaired.”
Researchers used the compound in mice genetically engineered to develop Alzheimer’s. Using a stain that attaches to the beta-amyloid plaques, the researchers saw up to 60 percent less staining after giving the mice the new drug, indicating that their brain plaques were dissolving.
Dissolving Beta-Amyloid Plaques
Working with the National Institutes of Health, the Penn researchers also tested the compound on brain tissue from people who'd died of Alzheimer’s. The lab results showed a 47 percent reduction in plaques in the inferior parietal cortex, an area of the brain associated with Alzheimer’s-related dementia.
Lastly, researchers gave the same toxin-protein pills to 15-month-old mice (80 years old in human years), bred to develop Alzheimer’s. They found that those mice had up to 70 percent fewer plaques in the hippocampus and 40 percent fewer in the cortex. Mice fed only lettuce capsules showed no reduction in disease plaques.
The also found fewer retinal plaques in the mice treated with the toxin-proteins.
“Really, no one knows whether the memory problems in people who have Alzheimer's disease are due to the dementia or problems with their eyes,” Daniell said. “Here we show it may be both and that we can dissolve the plaques through an oral route.”
Daniell and his team hope to expand their research to see whether their compound can not only remove plaques but also improve memory and function in mice with Alzheimer’s.