Research mines the mysteries of Alzheimer’s disease
When James Lee, armed with a bachelor’s degree in chemical engineering from the University of California-Berkeley, set out to obtain his doctorate from the University of Pennsylvania, he planned on someday working in the oil industry, perhaps in the refining realm.
He knew little beyond rudimentary biology when he came to work with a researcher at Penn who was studying cell mechanics in muscular dystrophy and red blood cells. But the experience would irrevocably alter the course of his work.
“I was thinking after I graduated, I wanted to do some more impactful research and still apply my previous engineering training,” Lee said.
Now an associate professor in the University of Missouri’s Bioengineering Department, Lee has spent the better part of a decade applying that training to help understand the effects or bring about the end of Alzheimer’s disease. And he recently received a $1.5 million grant from the National Institutes of Health to further his research between now and 2019.
Lee’s work focuses heavily on cell membranes and mechanical properties in neurodegenerative diseases such as Alzheimer’s disease. He received the most recent grant based on a proposal to study amyloid-beta peptide (A-beta), a marker protein found to accumulate in the brain of Alzheimer’s patients. He is working to determine how and why A-beta produces adverse effects on brain cells, including the star-shaped cells known as astrocytes, which provide structural and metabolic support to neurons and interact closely with the blood-brain barrier. The blood-brain barrier serves to insulate the brain from potentially harmful toxins and infections.
“It seems that A-beta has a direct impact on the property or the function of the blood-brain barrier,” Lee said. “We’ve only looked at the mechanical property. But we don’t know the biochemical reaction or the cellular pathways behind that change … and we’re trying to relate each step of the signaling pathway to that mechanical change.”
The mechanics potentially behind the disease are Lee’s specialty. Combining the cell mechanics with biology provides the opportunity to unveil the mechanisms from different angles and perspectives.
“People look at the [magnetic resonance imaging] and see the Alzheimer’s brain shrinks,” Lee said. “This is very physical, and then they will make measurements for the blood-brain barrier — it becomes leaky in the Alzheimer’s brain. That’s what I’m interested in. OK, this is leaky — how is it leaky? Why is it leaky?”
Providing the biochemical balance is Grace Sun, professor emerita of MU’s Biochemistry Department, who brings a wealth of experience and knowledge gleaned from years studying neurodegenerative disorders. Her work studying the enzyme phospholipase A2, which Lee and Sun’s work has shown to negatively affect the mitochondria responsible for energy production, made for a good partnership, as did their mutual respect for one another.
“When Dr. Lee came to the university, we met and talked about his interests and my interests, and I found out that his interests really reached some of the things I’m thinking about doing,” Sun said.
“We formulate some of the ideas together and the aims of how we can both approach the goal of understanding Alzheimer’s disease. He’s working on cells that cross the endothelium [a layer of cells lining blood and lymphatic vessels and serving as a barrier] and how that can be modified and how the enzyme responds to the modification. I’m more on the biochemical side of the story. We work with the enzyme and understand it more.”
For Sun, the research into Alzheimer’s is personal, having seen how the disease affected friends and family members as they began to age. The NIH estimates the malady affects as many as 5.1 million Americans annually, and Sun’s hope is that the research she and Lee are doing will at least provide solutions to slow its progression if not eliminate it completely sometime in the foreseeable future.
The recent NIH grant should help the process, and the timing couldn’t have been better. Sun recently oversaw a prestigious NIH program project grant on Alzheimer’s disease, which was funded to the tune of $12 million over the course of 12 years. But the project’s timeline came to a close last year. Fortunately, Lee’s grant should help pick up where the program project left off financially.
Lee already has started to hire some additional help for his lab, including postdoctoral fellow Devin Ridgley, who recently received his doctorate in biological systems engineering from Virginia Polytechnic Institute and State University after earning his bachelor’s at MU in Bioengineering. For Ridgley, the chance to work on a project with such potential real-world impact wasn’t an opportunity he could pass up, so he reached out to Lee via email after graduation.
“I actually got a newsletter about him getting this Alzheimer’s grant,” Ridgley said. “So I reached out and emailed him, and we’ve been talking for the last few months, and here I am.”
Lee said the team plans to use the funding to push even further than the proposal stated. Thus far, the research has involved work with the brains and brain cells of animals. Lee hopes to get a chance to work with human subjects in the near future, as well as working with different biophysical engineering techniques including atomic force microscopy, which uses a sharp-tipped instrument to probe and measure cell mechanics.
“We hope the results derived from our research can be translatable into clinical practice and treatments for the disease,” Lee said.
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