Could help efforts to find treatments for Alzheimer’s disease and other illnesses

Researchers at Washington University School of Medicine in St. Louis have discovered a new drug pathway that could potentially be used to help prevent Alzheimer’s dementia.

The accumulation of beta-amyloid in the brain is the first step in the development of Alzheimer’s dementia. Scientists have spent countless hours and millions of dollars finding ways to eliminate amyloid before cognitive symptoms appear, with largely disappointing results.

In this study, published August 24 in the journal Brain, researchers have found a way to increase the removal of waste from the brains of mice by increasing a genetic quirk known as read. This same strategy may also be effective for other neurodegenerative diseases characterized by the accumulation of toxic proteins, such as Parkinson’s disease, the researchers said.

Occasionally, the brain protein aquaporin 4 is synthesized with a small extra tail at its end. At first, Darshan Sapkota, PhD – who led this study when he was a postdoctoral researcher at the University of Washington, but is now an assistant professor of biological sciences at the University of Texas, Dallas – thought that this tail only represented nothing more than an occasional failure of quality control in the protein manufacturing process.

“We were studying this very wonky basic science question – ‘How are proteins made?’ “- and we noticed this funny thing,” said lead author Joseph D. Dougherty, PhD, a professor of genetics and psychiatry at the University of Washington and a former mentor at Sapkota. “Sometimes the protein synthesis machinery would blow through the stop sign at the end and create this extra chunk at the end of aquaporin 4. At first we thought it couldn’t be relevant. But then, we looked at the sequence of the gene, 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 disposal. That’s so at that point we got excited.

Scientists already knew that the cell’s protein-making machinery sometimes fails to stop where it should. When the machinery doesn’t shut down – a phenomenon known as readout – it creates extended forms of proteins that sometimes function differently than regular forms.

Sapkota and Dougherty created tools to see if the long form of aquaporin 4 behaved differently in the brain than the regular form. They found the long form – but not the short form – in the so-called terminal feet of astrocytes. Astrocytes are a kind of support cell that helps maintain the barrier between the brain and the rest of the body. Their feet wrap around tiny blood vessels in the brain and help regulate blood flow. The astrocyte feet are the perfect place if your job is to keep the brain free of unwanted proteins by flushing waste products out of the brain and into the bloodstream, where they can be washed away and eliminated.

Believing that increasing the amount of long aquaporin 4 might increase waste clearance, Sapkota screened 2,560 compounds for their ability to increase the reading of the aquaporin 4 gene. He found two: apigenin , a dietary flavone 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 understand the relationship. between long aquaporin 4 and beta-amyloid clearance.

The researchers studied mice genetically modified to have high levels of amyloid in their brains. They treated the mice with apigenin; sulfaquinoxaline; an inert liquid; or a placebo compound which has no effect on the reading. Mice treated with apigenin or sulphaquinoxaline eliminated beta-amyloid much faster than those treated with either of the two inactive substances.

“There is a lot of data that indicates that reducing amyloid levels by just 20% to 25% stops amyloid buildup, at least in mice, and the effects we saw were within that range,” Cirrito said. “It tells me that this could be a new approach to treating Alzheimer’s disease and other neurodegenerative diseases that involve protein aggregation in the brain. There is nothing to say that this process is specific to beta-amyloid. It may improve, for example, the clearance of alpha-synuclein, too, which could benefit people with Parkinson’s disease.”

Sulphaquinoxaline is not safe for humans. Apigenin is available as a dietary supplement, but it’s unclear how much enters the brain, and Cirrito cautions against consuming large amounts of apigenin in an effort to ward off Alzheimer’s disease. Researchers are working to find better drugs that influence the production of the long form of aquaporin 4, by testing several sulfaquinoxaline derivatives and additional compounds.

“We’re looking for something that could be quickly translated into the clinic,” Sapkota said. “Just knowing that it can be targeted by a drug is a useful hint that there will be something we can use.”

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