C. elegans is a nematode, a slender, transparent worm only
about a millimeter long, that lives in soil, where it eats bacteria.
Since the 1970s, this worm has been viewed as a model organism, the
subject of numerous studies because it is a much simpler system than us
humans for studying cell biology and diseases.
“As humans, we have immense genetic diversity and such complex diets
that it makes it really hard to decipher how one dietary factor is
affecting the onset and progression of Alzheimer’s,” Tanis said. “That’s
where the worms are amazing. The worms we use all have exactly the same
genetic background, they react to amyloid beta like humans do, and we
can exactly control what they eat, so we can really get down to the
molecular mechanisms at work.”
In the brains of humans with Alzheimer’s, the buildup of amyloid beta
over the years causes toxic effects in cells, resulting in reduced
energy, fragmentation of the mitochondria — the cells’ power plants, and
oxidative stress from an excess of free radicals. The same thing
happens in C. elegans, Tanis said, but in a matter of hours. Amyloid beta causes paralysis in the worms.
“The read-out is black or white — the worms are either moving or they
are not,” Tanis said. “When we gave vitamin B12 to the worms that were
vitamin B12 deficient, paralysis occurred much more slowly, which
immediately told us that B12 was beneficial. The worms with B12 also had
higher energy levels and lower oxidative stress in their cells.”
The team determined that vitamin B12 relies on a specific enzyme
called methionine synthase to work. Without the presence of that enzyme,
B12 has no effect, Tanis said. Also, 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 amyloid beta levels in the
worms.
Tanis team power
Tanis credits her students for their hard work and contributions. The
first author on the research article, Andy Lam, is pursuing a dual
degree at UD — a doctorate in biological sciences and a master of
business administration. He spent years working on the laboratory
protocols critical to the study. He ran dozens and dozens of experiments
and documented observations overnight numerous times.
A future goal is to automate these experiments using a
high-throughput system at UD’s Bio-Imaging Center coupled with deep
learning analysis to detect if the worms are moving or not. That would
allow the team to more rapidly examine the interactions between diet and
genetics.
“We’ve essentially identified this molecular pathway and we’re
looking to see what else it activates,” Tanis said. “Can B12 be
protective for multiple neurodegenerative diseases such as ALS and
Parkinson’s? We’re looking into it.”
While Kirsten Kervin graduated from UD with her master’s degree and
is now a research scientist at WuXi AppTec in Philadelphia, it was her
astute observation about C. elegans that set the project into motion.
“That initial observation opened up an entirely different world,”
Tanis said, “which is somehow the story of my research career here at
UD. I came here thinking I would be studying one thing, but now I’m
studying another. So it hasn’t been straightforward, but it has opened
up an entirely new research area we are pursuing.”
That “we” working on this project now includes two graduate students,
a postdoctoral research associate, three undergraduate students and
collaborations with the Bio-Imaging Center and multiple UD labs.
“Right now, there is no effective treatment for Alzheimer’s disease,”
Tanis said. “There are certain factors that you cannot change – you
cannot change the fact that you age, and you cannot change a genetic
predisposition to Alzheimer’s disease. But one thing you can control is
what you eat. If people could change their diet to affect the onset of
disease, that would be fantastic. That’s something my lab is excited to
continue to explore.”
The research is published in the Sept. 28 issue of Cell Reports.
The work was supported through grants from the University of Delaware
Research Foundation and the NIH-funded Delaware INBRE program, where
Tanis was a pilot investigator, and an NIH-funded Alzheimer’s supplement
grant.
Article by Tracey Bryant;
photos by Kathy F. Atkinson, Tanis Lab and UD Bio-Imaging Center
Published Sept. 28, 2021