While narrowing down an exact cause for diseases like Alzheimer’s remains in the works, expanding treatment efforts is the greatest line of defense against further damage as of now. To that end, Washington University School of Medicine researchers say they’ve discovered a new potential pathway that can be targeted by drugs to remove toxins from the brain.
So far, it has been well-studied that amyloid beta accumulation is an early marker of Alzheimer’s disease development. As a result, scientists have consistently attempted to find ways to remove this compound and stop degeneration before things go too far, but this has remained unsuccessful. Now, this team has successfully found a path to clearing toxic waste in mice brains through a genetic peculiarity called readthrough.
This describes when aquaporin 4, a brain protein, is synthesized with an additional extended tail on the end of the protein. The team disregarded this at first, putting it off as just poor quality from protein manufacturing.
“We were studying this very wonky basic science question — ‘How do proteins get made?’ — and we noticed this funny thing,” says senior author Joseph D. Dougherty, PhD, a Washington University professor of genetics and of psychiatry, in a statement. “Sometimes the protein-synthesizing machinery blew right through the stop sign at the end and made this extra bit on the end of aquaporin 4. At first, we thought it couldn’t possibly be relevant. But then we looked at the gene sequence, and it was conserved across species. And it had this really striking pattern in the brain: It was only in structures that are important for waste clearance. So that’s when we got excited.”
The researchers developed tools to identify differences in behavior from the longer protein and the protein of normal size. They discovered that the long protein was able to use its extension to wrap around blood vessels, regulating blood flow and possibly helping to promote waste clearance.
To delve into this, the team screened 2,560 compounds for the ability to enhance readthrough of aquaporin 4. Apigenin, a dietary compound found in chamomile, parsley, onions, etc, and sulphaquinoxaline, a veterinary antibiotic used in meat and poultry industries were the two found to do the job.
Mice genetically engineered to have high amounts of amyloid were treated with either apigenin, sulphaquinoxaline, an inert liquid, or a placebo. The rodents treated with either compound were found to promote readthrough were able to clear amyloid beta far more efficiently than those treated with the placebo or liquid.
While these findings offer valuable information for future neurology efforts related to Alzheimer’s dementia, more work with this mechanism is needed. A large limitation to this work is that sulphaquinoxaline is not safe for humans, and while apigenin is available as a supplement for purchase, required dosages and brain absorption remains unknown. Due to this, the research team is working to find drugs best suitable for humans that target the same pathway and plan to test derivatives of the compounds used in this study.
The study is published in the journal Brain.