Fight Aging!

Researchers here report on an interesting discovery relating to the way in which aquaporin-4 functions in clearance of molecular waste from the brain. An uncommon isoform of aquaporin-4 has a role in clearing excess amyloid-β, and possibly many other forms of molecular waste. Given that a failure of clearance of molecular waste from the brain is apparently involved in many neurodegenerative conditions, approaches that enhance clearance are promising. Increased amounts of this more effective isoform can be achieved via a variety of strategies in mice, and in mice engineered to generate excess amyloid-β, this results in a reduction of amyloid-β in the brain. This is quite interesting, but further work is required to determine a useful way to implement this shift in protein isoforms in humans.

Every once in a while, the brain protein aquaporin 4 is synthesized with an extra little tail on the end. Scientists already knew that the cell's protein-building machinery occasionally fails to stop where it should. When the machinery doesn't stop - a phenomenon known as readthrough - it creates extended forms of proteins that sometimes function differently than the regular forms. "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."

Researchers found the long form - but not the short one - in the so-called endfeet of astrocytes. Astrocytes are a kind of support cell that help maintain the barrier between the brain and the rest of the body. Their endfeet wrap around tiny blood vessels in the brain and help regulate blood flow. Astrocytic endfeet are the perfect place to be if your job is to keep the brain free of unwanted proteins by flushing waste out of the brain and into the bloodstream, where it can be carried away and disposed of.

Thinking that increasing the amount of long aquaporin 4 might increase waste clearance, researchers screened 2,560 compounds for the ability to increase readthrough of the aquaporin 4 gene. They found two: apigenin, a dietary flavone, and sulphaquinoxaline, a veterinary antibiotic. Sulphaquinoxaline is not safe for use in people. Apigenin is available as a dietary supplement, but it's not known how much gets into the brain. The researchers studied mice genetically engineered to have high levels of amyloid in their brains. They treated the mice with apigenin; sulphaquinoxaline; an inert liquid; or a placebo compound that has no effect on readthrough. Mice treated with either apigenin or sulphaquinoxaline cleared amyloid beta significantly faster than those treated with either of the two inactive substances.

"There's a lot of data that says reducing amyloid levels by just 20% to 25% stops amyloid buildup, at least in mice, and the effects we saw were in that ballpark. This could be a novel approach to treating Alzheimer's and other neurodegenerative diseases that involve protein aggregation in the brain. There's nothing that says this process is specific for amyloid beta. It may be enhancing, say, alpha-synuclein clearance, too, which could benefit people with Parkinson's disease."

Link: https://medicine.wustl.edu/news/study-points-to-new-approach-to-clearing-toxic-waste-from-brain/