More than 7 million Americans over the age of 65 live with Alzheimer's. For years, scientists researching the disease have believed it begins when fragments of amino acids begin aggregating in brains, triggering a cascade effect that leads to plaque formation, degradation and eventual neuron death. But recent studies are beginning to call this central hypothesis into question - and Binghamton research might change fundamental ideas about how Alzheimer's works.
Chemistry Professor Wei Qiang has been exploring Alzheimer's since he joined the Harpur College faculty more than a decade ago. He investigates the very fragments, called Amyloid-beta peptides, thought to mark the beginning point of Alzheimer's. The central problem guiding Qiang's research lately isn't just how their aggregation disrupts cell membranes, but also how those fragments begin to form structures in the first place.
"The specific question is how these individual chains start to assemble. Which part of them assembles first, which part is assembled later, and which part, during this process, interacts with the lipids causing the membrane disordering," Qiang said. "That's the question we're answering."
Studying disordered systems
Qiang was recently listed as one of 29 Binghamton researchers in the top 2% of scientists around the world in a study by Stanford University. His work, which uses a technique called solid-state nuclear magnetic resonance (NMR) spectroscopy, has received around $2 million from the NIH's National Institute for General Medical Sciences since 2018, on top of additional funding from the S.H. Ho Research Foundation.
"Professor Wei Qiang's research using solid-state NMR spectroscopy to study Alzheimer's disease exemplifies the kind of high-impact science that defines Harpur College of Arts and Sciences," said Celia Klin, dean of Harpur College. "His research not only advances our fundamental understanding of neurodegenerative diseases such as Alzheimer's, but also opens up promising avenues for therapeutic development. His research and teaching are an asset to our educational, scholarly and public mission."
NMR spectroscopy is a versatile technique, and it is ideal for viewing systems that cannot form crystals.
"The system that we are particularly interested in doesn't have a very well-ordered structure yet, because it's before the formation of that very well-ordered structure," Qiang said. "We're basically looking at a very dynamic, heterogeneous system."
Using NMR spectroscopy, Qiang essentially takes snapshots of amyloid aggregation at different stages. Initially, his research began with artificially synthesized membrane models, chemically assembled in the lab, but now he is progressing into real cell systems.
Cells are finicky and notoriously difficult to keep alive, meaning the living models that Qiang uses must be kept in a state of deep cryogenic freeze.
"At 4 degrees Celsius, which is like the temperature of a fridge, you can keep the cell alive for at most five hours," he said. "You have to have done every experiment within five hours. Plus, the solid-state NMR sensitivity is low, so there's not very much information you can get."
Because of this, during the past few years, Qiang has traveled to the National Magnetic Lab in Florida to conduct his experiments. There, his team can obtain NMR spectrums at cryogenic-level temperatures, with significantly enhanced sensitivity. The goal with these commutes and experiments is to eventually move from undifferentiated cell lines to work on full, real neurons.
"We're fundamental studies. The information we get from here will help for the design of an agent that could prevent the process. It's like any kind of drug design you would have for pharmaceutical companies," Qiang said. "If you know the protein structure and you find the pocket that's important for binding the drugs, that's the general workflow for pharmaceutical companies. It's the same kind of information that we provide from our study."
But because Qiang is working in the earliest stages of the process, it's difficult to forecast what kinds of pockets or protein structures would be relevant.
"The challenge here is that there's no structure available, and because it's an early-stage event, there's probably not a very well-defined structure," he said. "Our study provides this similar information, but on a more challenging system that is disordered."
Reframing an old hypothesis
In tandem with advancing to the study of real neurons, Qiang is also aiming to understand how the amyloid structures - which are called fibrils - proliferate in the brain. Proteins rely on structure to be functional, but fragmented peptides can take on many structures. This structural polymorphism is thought to be relevant in the development of Alzheimer's, calling into question the longtime cascade hypothesis.
"People think there's a very linear kind of workflow, from the aggregation of Amyloid-beta to the downstream clinical symptoms. This has been challenged, because there are a lot of failures in this field for drug design that's based on targeting particular structures of the Amyloid-beta aggregates," Qiang said.
He believes the results from his group's research may help modify that central hypothesis to account for more chaotic systems, while new fundamental findings could also contribute to the development of improved drugs.
"We're trying to understand why and how structural polymorphism is important," he said. "There's not only one structure that you should target, but we should understand how this diversity changes within the whole system."
A longtime project
Qiang first fell in love with NMR spectroscopy at Tsinghua University in China. At the time, he was the only student in his class to conduct research as an undergraduate.
"It's problem-driven. You have something you try to solve, you go back to the theory and you develop something," he said. "To me, that's the beauty of NMR spectroscopy. It has the capability to always allow you to fine-tune the current method and direct it to the specific question you're interested in."
In his field, he finds new questions arising just as quickly as answers do, if not faster. What has kept Qiang interested in pursuing those answers over the years is his curiosity, further stoked by the possibilities and flexibility of spectroscopy.
"We started from a single model system. Now we're moving into cells. I'm happy that over 10 years, we're receiving continuous funding for this direction," he said. "It's a challenging direction, and I would say we're moving at a steady pace."
Beyond the lab he has established at Binghamton, Qiang also appreciates the community and collaborative environment he has found at the University.
"Everybody is focused on their project, but if you have any questions out of your expertise that you don't understand, you can always find somebody to ask here," he said.
