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Could aid efforts to find treatments for Alzheimers, other diseases

An extended form of the protein aquaporin 4 (red) lines the edges of tiny blood vessels in the brain. Cell nuclei are visible in blue. Researchers at Washington University School of Medicine in St. Louis have found a new druggable pathway that enhances the amount of long aquaporin 4 near blood vessels and increases the clearance of waste from the brain. The findings potentially could lead to new therapies to prevent Alzheimers dementia.

Researchers at Washington University School of Medicine in St. Louis have found a new druggable pathway that potentially could be used to help prevent Alzheimers dementia.

Amyloid beta accumulation in the brain is the first step in the development of Alzheimers dementia. Scientists have poured countless hours and millions of dollars into finding ways to clear amyloid away before cognitive symptoms arise, with largely disappointing results.

In this study, published Aug. 24 in the journal Brain, researchers found a way to increase clearance of waste products from the brains of mice by ramping up a genetic quirk known as readthrough. This same strategy also may be effective for other neurodegenerative diseases characterized by the buildup of toxic proteins, such as Parkinsons disease, the researchers said.

Every once in a while, the brain protein aquaporin 4 is synthesized with an extra little tail on the end. At first, Darshan Sapkota, PhD who led this study while a postdoctoral researcher at Washington University but is now an assistant professor of biological sciences at the University of Texas, Dallas thought this tail 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 do proteins get made? and we noticed this funny thing, said senior author Joseph D. Dougherty, PhD, a Washington University professor of genetics and of psychiatry, and Sapkotas former mentor. 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 couldnt 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 thats when we got excited.

Scientists already knew that the cells protein-building machinery occasionally fails to stop where it should. When the machinery doesnt stop a phenomenon known as readthrough it creates extended forms of proteins that sometimes function differently than the regular forms.

Sapkota and Dougherty created tools to see whether the long form of aquaporin 4 behaved differently in the brain than the regular form. They 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, Sapkota screened 2,560 compounds for the ability to increase readthrough of the aquaporin 4 gene. He found two: apigenin, a dietary flavone found in chamomile, parsley, onions and other edible plants; and sulphaquinoxaline, a veterinary antibiotic used in the meat and poultry industries.

Sapkota and Dougherty teamed up with Alzheimers researchers and co-authors John Cirrito, PhD, an associate professor of neurology, andCarla Yuede, PhD, an associate professor of psychiatry, of neurology and of neuroscience, to figure out the relationship between long aquaporin 4 and amyloid beta clearance.

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.

Theres 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, Cirrito said. That tells me that this could be a novel approach to treating Alzheimers and other neurodegenerative diseases that involve protein aggregation in the brain. Theres nothing that says this process is specific for amyloid beta. It may be enhancing, say, alpha-synuclein clearance, too, which could benefit people with Parkinsons disease.

Sulphaquinoxaline is not safe for use in people. Apigenin is available as a dietary supplement, but its not known how much gets into the brain, and Cirrito cautions against consuming large amounts of apigenin in an attempt to stave off Alzheimers. The researchers are working on finding better drugs that influence the production of the long form of aquaporin 4, testing several derivatives of sulphaquinoxaline and additional compounds.

Were looking for something that could be quickly translated into the clinic, Sapkota said. Just knowing that its targetable at all by a drug is a helpful hint that theres going to be something out there we can use.

Sapkota D, Florian C, Doherty BM, White KM, Reardon KM, Ge X, Garbow JR, Yuede CM, Cirrito JR, Dougherty JD. Aqp4 stop codon readthrough facilitates amyloid- clearance from the brain. Brain. Aug. 24, 2022. DOI:10.1093/brain/awac199

This work was supported by the National Institute of Neurological Disorders and Stroke, grant number 1R01NS102272; the Mallinckrodt Institute of Radiology; the Hope Center for Neurological Disorders; the National Institute on Aging, grant numbers K99AG061231 and R01AG064902; Coins for Alzheimers Research Trust; and the Rotary Club International.

About Washington University School of Medicine

WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,700 faculty. Its National Institutes of Health (NIH) research funding portfolio is the fourth largest among U.S. medical schools, has grown 54% in the last five years, and, together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,790 faculty physicians practicing at over 60 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Childrens hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.

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This entry was posted on August 27, 2022 at 2:08 am and is filed under Genetic medicine. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed. |