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Worms don’t move when they have Alzheimer’s disease. Still, something helped the worms with the disease keep their movement in Professor Jessica Tanis’s lab at the University of Delaware.
By solving the mystery, Tanis and his team have provided new clues about the potential impact of diet on Alzheimer’s disease, the dreaded degenerative disease of the brain that afflicts more than 6 million Americans.
A few years ago, Tanis and his team began to study the factors affecting the onset and progression of Alzheimer’s disease. They were doing genetic research with C. elegans, a tiny groundworm that is the subject of many studies.
The expression of beta-amyloid, a toxic protein involved in Alzheimer’s disease, paralyzes worms within 36 hours of adulthood. While worms in a Petri dish in Tanis’ lab were completely still, worms of the same age in the adjacent Petri dish still had their movement, documented by scientists as “body curvature.”
“It was an observation made by Kirsten Kervin, a master’s student,” said Tanis, assistant professor in the department of biological sciences at UD. “She repeated the experiment over and over again, with the same results.”
After years of research, the team finally found a significant difference, Tanis said. While all of the worms were grown on a diet of E. coli, it turns out that a strain of E. coli had higher levels of vitamin B12 than the other. Although Tanis’ work focused on genetic factors at the time, she shifted her research to examine this vitamin and its protective role.
Learn verses
C. elegans is a nematode, a thin, transparent worm only about a millimeter long, that lives in the soil, where it feeds on bacteria. Since the 1970s, this worm has been considered a model organism, the subject of many studies because it is a much simpler system than us humans for studying cell biology and disease.
“As humans, we have immense genetic diversity and diets so complex that it’s really hard to decipher how a dietary factor affects the onset and progression of Alzheimer’s disease,” said Tanis. . “This is where worms are amazing. The worms we use all have the exact same genetic makeup, they react to beta amyloid just like humans do, and we can control exactly what they eat, so that we can really focus on the molecular mechanisms at work. “
In the brains of humans with Alzheimer’s disease, the build-up of beta-amyloid over the years causes toxic effects in cells, resulting in reduced energy, fragmentation of mitochondria – the powerhouses of cells and oxidative stress due to an excess of free radicals. The same thing happens in C. elegans, Tanis said, but within hours. Beta-amyloid causes paralysis in worms.
“The reading is black or white – the worms move or they don’t,” Tanis said. “When we gave vitamin B12 to vitamin B12 deficient worms, the paralysis occurred much more slowly, which immediately told us that B12 was beneficial. Worms with B12 also had higher energy levels. higher and lower oxidative stress in their cells. “
The team determined that vitamin B12 depends on a specific enzyme called methionine synthase to function. Without the presence of this enzyme, B12 has no effect, Tanis said. Additionally, adding the vitamin to the diet only worked if the animals were deficient in B12. Giving more B12 to animals with healthy levels does not help them in any way. The team also showed that vitamin B12 had no effect on beta-amyloid levels in the worms.
The power of the Tanis team
Tanis thanks his students for their hard work and contributions. The first author of the research paper, Andy Lam, is pursuing a dual degree at UD – a doctorate in biological sciences and a master’s degree in business administration. He spent years working on essential laboratory protocols for the study. He has conducted dozens and dozens of experiments and documented overnight sightings on numerous occasions.
A future goal is to automate these experiments using a high-throughput system at the DU’s bio-imaging center coupled with deep learning analysis to detect whether the worms are moving or not. This would allow the team to more quickly examine the interactions between diet and genetics.
“We’ve basically identified this molecular pathway and we’re looking to see what else it activates,” Tanis said. “Can B12 protect against multiple neurodegenerative diseases such as ALS and Parkinson’s disease?” We are looking into the matter. “
While Kirsten Kervin graduated from UD with her masters and is now a researcher at WuXi AppTec in Philadelphia, it was her astute observation on C. elegans that started the project.
“This initial sighting opened up an entirely different world,” Tanis said, “which is sort of the story of my research career here at UD. I came here thinking I would study one thing, but now I am studying another. has not been easy, but it has opened up a whole new area of research that we are pursuing. “
This “we” working on this project now includes two graduate students, a postdoctoral research associate, three undergraduate students and collaborations with the Center for Bioimaging and several UD laboratories.
“Currently, there is no effective treatment for Alzheimer’s disease,” Tanis said. “There are certain factors you can’t change – you can’t change the way you get older, and you can’t change a genetic predisposition to Alzheimer’s disease. But one thing you can control is what you eat. If people could change their diets to affect the onset of disease, that would be fantastic. This is something my lab is excited to continue to explore. “
The work was supported by grants from the University of Delaware Research Foundation and the NIH-funded Delaware INBRE program, where Tanis was a pilot researcher, and by an NIH-funded Alzheimer’s supplement grant.
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