Scientists at Rice University are using fluorescence lifetimes to shed new light on a peptide associated with Alzheimer’s disease, which the Centers for Disease Control and Prevention estimates will affect nearly 14 million people in the U.S. by 2060.
Through a new approach using time-resolved spectroscopy and computational chemistry, Angel Marti and his team found experimental evidence of an alternative binding site in amyloid-beta aggregates, opening the door to the development of new treatments for Alzheimer’s and other diseases associated with amyloid deposits. .
The study is published in Chemistry.
Amyloid plaque deposits in the brain are a hallmark of Alzheimer’s disease. “Amyloid-beta is a peptide that accumulates in the brains of people with Alzheimer’s disease, forming these supramolecular nanoscale fibers, or fibrils,” said Marty, director of chemistry, bioengineering, and materials science and nanoengineering and faculty. Emerging Scholars Program. “Once they grow large enough, these fibrils precipitate and form what we call amyloid plaques.
Want more breaking news?
Subscribe Technology networks‘ Daily Newsletter, delivering fresh science news to your inbox every day.
Subscribe for free
“Understanding how molecules bind to amyloid-beta in general is important not only for developing drugs that better bind to its aggregates, but also for figuring out who the other players are that contribute to brain tissue toxicity,” he added.
The Marty group had already identified the first binding site for amyloid-beta deposits by showing how metal dye molecules were able to bind to the pockets formed by the fibrils. The ability of molecules to fluoresce, or emit light, when excited under a spectroscope indicated the presence of a binding site.
Time-resolved spectroscopy, which the lab used in its latest discovery, “is an experimental technique that looks at the time molecules spend in an excited state,” Marty said. “We excite the molecule with light, the molecule absorbs the energy from the light photons and goes into an excited state, a more energetic state.”
This energetic state is responsible for the fluorescent glow. “We can measure the time the molecules spend in the excited state, called the lifetime, and then we use that information to assess the binding equilibrium of small molecules to amyloid-beta,” Marty said.
In addition to the second binding site, the University of Miami lab and collaborators discovered that multiple fluorescent dyes bind to amyloid deposits in an unexpected way.
“These findings are allowing us to map the binding sites on amyloid-beta and record the amino acid structures required for the formation of binding pockets in amyloid-beta fibrils,” Marty said.
The fact that time-resolved spectroscopy is sensitive to the surrounding environment of the dye molecule enabled Marty to infer the presence of a second binding site. “When the molecule is free in solution, its fluorescence has a specific lifetime that is due to its environment. However, when the molecule is bound to amyloid fibers, the microenvironment is different and consequently the fluorescence lifetime,” he explained. “For the molecule bound to amyloid fibers, we observed two distinct fluorescence lifetimes.
“The molecule did not bind to a unique site on amyloid-beta but to two different sites. And that was very interesting because our previous studies indicated only one binding site. This is because we could not see all the components with the techniques we used before, ” he added.
The discovery inspired further experimentation. “We decided to look at it further using not only the probe we designed, but also other molecules that have been used in inorganic photochemistry for decades,” he said. “The idea was to find a negative control, a molecule that doesn’t bind to amyloid-beta. But what we found was that these molecules that we didn’t expect to bind to amyloid-beta actually bound to it with decent affinity.”
Marty said the findings will also affect the study of “many diseases associated with other types of amyloids: Parkinson’s, amyotrophic lateral sclerosis (ALS), type 2 diabetes, systemic amyloidosis.”
Understanding the binding mechanism of amyloid proteins is also useful for studying nonpathogenic amyloids and their potential applications in drug development and materials science.
“There are functional amyloids that our bodies and other organisms produce for a variety of reasons that are not related to diseases,” Marty said. “There are organisms that produce amyloids that have antibacterial effects. There are organisms that produce amyloids for structural purposes, to create barriers, and others that use amyloids for chemical storage. The study of nonpathogenic amyloids is an emerging field of science, so This is another way we can help develop our findings.”
Reference: Jiang B, Umezaki U, Augustine A, et al. Deconvoluting binding sites on amyloid nanofibrils using time-resolved spectroscopy. Chemistry. 2023. doi: 10.1039/D2SC05418C
This article has been republished from: Materials. Note: Content may have been edited for length and content. For more information, please contact the source cited.