Researchers from Washington University School of Medicine in St. Louis have discovered a new druggable pathway that could potentially be used to help prevent dementia in Alzheimer’s disease.The accumulation of amyloid beta in the brain is thought to be the first step in the development of dementia in Alzheimer’s disease. Researchers have invested countless hours and millions of dollars in finding ways to clear amyloid before cognitive symptoms appear. Unfortunately, however, the results were largely disappointing.
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In this study, scientists discovered a way to increase the removal of waste from the brains of mice by boosting a genetic quirk known as a “reading breakthrough.” According to the researchers, this same strategy may also be effective against other neurodegenerative diseases characterized by toxic protein buildup, such as Parkinson’s disease. The study was published in Brain on August 24, local time.
Every so often, the brain protein aquaporin 4 is synthesized, with an extra little tail at the end. At first, Dr Darshan Sapkota thought the tail was nothing more than an occasional quality control failure during protein manufacturing. Sapkota led the research as a postdoctoral fellow at the University of Washington, but is now an assistant professor of biological sciences at the University of Texas at Dallas.
“We’re looking at this very quirky basic science question — ‘how proteins are made’ –” said Joseph D. – and we noticed this interesting thing. Sometimes the protein synthesis machinery goes right through the stop sign at the end to make this extra site at the end of aquaporin 4, at first we thought it couldn’t possibly have anything to do with it. But then We looked at the genetic sequence and it’s conserved across species. And it has this really amazing pattern in the brain. It’s only in structures that are important for removing waste. So that’s when we get excited .”
Scientists have known that the cell’s protein-building machinery occasionally fails where it should. When the machine doesn’t stop — a phenomenon known as “read-through” — it creates expanded forms of proteins that sometimes function differently than regular forms.
Sapkota and Dougherty created special tools to see whether the long form of aquaporin 4 behaves differently in the brain than the regular form. They found the long form — but not the short form — in so-called astrocyte endings. Astrocytes are supportive cells that help maintain the barrier between the brain and the rest of the body. Their end caps wrap around tiny blood vessels in the brain that help regulate blood flow. If your job is to flush waste out of the brain and into the bloodstream, where it’s carried away and processed, then the inside of the astrocyte tip is the perfect place.
Sapkota believes that increasing the amount of long aquaporin 4 may increase waste removal. So he screened 2,560 compounds to see if they could increase the read throughput of the aquaporin 4 gene. As a result, he found two compounds: apigenin, a dietary flavonoid found in chamomile, parsley, onions and other edible plants; and sulfaquinoxaline, a veterinary antibiotic used in the meat and poultry industries.
Sapkota and Dougherty teamed up with Alzheimer’s disease researchers and co-authors John Cirrito, PhD, associate professor of neurology, and Carla Yuede, PhD, associate professor of psychiatry, neurology, and neuroscience to unravel the link between aquaporin 4 and amyloid beta clearance Relationship.
Scientists have studied mice genetically engineered to have high levels of amyloid in their brains. They treated the mice with apigenin, sulfaquinoxaline, an inert liquid or a placebo compound that had no effect on read-through breakthroughs. Mice treated with apigenin or sulfaquinoxaline cleared amyloid beta significantly faster than mice treated with either of the two inactive substances.
“There’s a lot of data that, at least in mice, reducing amyloid levels by 20 to 25 percent stops amyloid buildup, and the effects we’re seeing are in that range,” Cirrito said. , which could be a new way to treat Alzheimer’s disease and other neurodegenerative diseases that involve protein aggregation in the brain. There’s no indication that this process is targeting amyloid beta. It may also be enhancing, like Said, the clearance of alpha-synapsin, which may benefit Parkinson’s patients.”
Sulfaquinoxaline is not safe for human use. Apigenin is available as a dietary supplement but it is not known how much gets into the brain. Cirrito warns against consuming large amounts of apigenin to ward off Alzheimer’s disease. Scientists are working to find better drugs to affect the production of the long form of aquaporin 4, and are also testing several sulfaquinoxaline derivatives and other compounds.
“We’re looking for something that can be quickly translated into the clinic. Just knowing that it can be targeted by a drug is a useful hint that there will be something out there that we can use,” Sapkota said.