Drug repairs systems that drain Alzheimer's-causing waste from brain


A team of undergraduates has shown that an experimental drug known as Yoda1 may help misshapen mouse brains drain cranial waste plus neurotoxins that cause Alzheimer’s disease and other forms of dementia.

“The brain’s lymphatic system is one of the hottest research areas in all of medicine right now because it has only been re-discovered in the past ten years, and it’s clearly vital to healthy brain function and, very likely, developing dementias like Alzheimer’s,” said the senior author.

“The team for this study took a very out-of-the-box approach and studied a human cranial facial disorder called craniosynostosis that creates excess pressure inside the skull,” added the senior author of the study, who conducted the research with honors undergraduate students from the departments of Genetics and Cell Biology and Neuroscience.

“We started by showing this extra pressure damaged the brain’s lymphatic system, inhibiting cerebrospinal fluid movement and thus the ability to drain waste. We then went on to find a way to prevent and even partially reverse the problem.”

The study, published in the Journal of Clinical Investigation, examined mice with craniosynostosis, a skull malformation that increases pressure inside the skull and reduces the ability to form, maintain and use the network of lymphatic vessels that help drain brain waste and plaque-laden cerebrospinal fluid. In addition, the ability of cerebrospinal fluid to perfuse into the brain and clear waste to surrounding lymphatic vessels, known as the glymphatic system, was impeded.

Using a mouse model for familial Alzheimer’s disease, the addition of craniosynostosis and associated impairments to the lymphatic and glymphatic systems caused a significant increase in plaque burden in the brain.

To counteract these deficits, the investigators turned their attention to a drug called Yoda1, which activates a force-sensing ion channel known as Piezo1. This drug reduced intracranial pressure and allowed newborn mice with craniosynostosis to develop and maintain normal lymphatic vasculature that supported the ability of cerebrospinal fluid to perfuse into the brain and drain its waste to lymph nodes. Researchers also found that using Yoda1 in previously untreated aged adult mice improved meningeal lymphatic and glymphatic functions, making brain waste-clearance systems that had looked old appear young again.

Both the brain’s associated lymphatic system and the existence of Piezo mechanosensitive ion channels are recent discoveries that have generated excitement and research.

Yoda1 has yet to undergo human trials, but researchers everywhere are seeking effective Alzheimer’s treatments. The degenerative disease, along with other forms of dementia, is becoming more common as the American population ages.

“Many labs are working in this space because there’s still so much to learn about the lymphatic system that surrounds the brain,” the author said. “There’s particular excitement because research to date has found that it degenerates dramatically with age, so any breakthrough that maintains its function might help prevent age-related cognitive decline.”

“The next step for us in this line of research is to discover the mechanism Yoda1 uses to improve vessel function,’’ the author added. “Is it working directly on the vessels by stimulating Piezo1, stimulating a growth factor in the environment or doing something else?”

https://www.jci.org/articles/view/171468

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fpiezo1-agonist-restores&filter=22

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