Research shows that protein plaques associated with Alzheimer’s are more sticky than thought

Research shows that protein plaques associated with Alzheimer’s are more sticky than thought

Scientists' discovery could lead to new Alzheimer's therapies

A researcher in Rice’s Angel Martí lab holds a vial of fluorescent dye molecules in solution. Using time-resolved spectroscopy, which tracks the fluorescence lifetime of dye molecules, Martí and colleagues describe a second binding site on amyloid-beta deposits associated with Alzheimer’s disease, opening the door to the development of new therapies. Credit: Gustavo Raskosky/Rice University

Rice University scientists are using lifetime fluorescence to shed new light on a peptide involved in Alzheimer’s disease, which the Centers for Disease Control and Prevention estimates will affect nearly 14 million people in the US by 2060.

Through a new approach using time-resolved spectroscopy and computational chemistry, Angel Martí and his team obtained experimental evidence of another binding site on amyloid-beta aggregates, opening the door to the development of new therapies for Alzheimer’s and other diseases that associated with amyloid deposits. .

The study is published in Chemical Science.

Amyloid plaque deposits in the brain are a key feature of Alzheimer’s. “Amyloid-beta is a peptide that aggregates in the brains of people suffering from Alzheimer’s disease, forming supramolecular nanoscale fibers, or fibrils” said Martí, professor of chemistry, bioengineering, and material science and nanoengineering and faculty director of the Rice. Emerging Scholars Program. “When they grow enough, these fibrils precipitate and form what we call amyloid plaques.

“Understanding how molecules generally bind to beta-amyloid is extremely important, not only for developing drugs that bind with better affinity to its aggregates, but also to find out who the other players are which contributes to brain tissue toxicity,” he said.

Scientists' discovery could lead to new Alzheimer's therapies

A fluorescent dye molecule binds to the second binding site on the amyloid-beta protein fibril. Credit: The Prabhakar Group/University of Miami)

The Martí group had already identified the first binding site for amyloid-beta deposits by discovering how metallic dye molecules were able to bind to pockets formed by the fibrils. The ability of the molecules to fluoresce, or emit light when passed under a spectroscope, indicated the presence of the binding site.

Time-resolved spectroscopy, which the laboratory used in its latest discovery, is an experimental technique that looks at the time spent by molecules in an excited state,” said Martí. “We excite the molecule with light, the molecule absorbs the energy from the light photons and it gets an excited state, a more energetic state.”

This energy state is responsible for the fluorescent glow. “We can measure the time that molecules spend in the excited state, known as the lifetime, and then we use that information to estimate the binding equilibrium of small molecules to amyloid-beta,” said Martí.

In addition to the second binding site, the lab and collaborators from the University of Miami noted that multiple fluorescent dyes were not expected to bind to amyloid deposits.

“These results allow us to create a map of binding sites in beta-amyloid and record the amino acid compositions required to form binding pockets in amyloid-beta fibrils,” said Martí.

Scientists' discovery could lead to new Alzheimer's therapies

A close-up view shows a fluorescent dye molecule bound to a second binding site known as amyloid-beta aggregates. Credit: The Prabhakar Group/University of Miami

Because time-resolved spectroscopy is sensitive to the environment around the dye molecule, it enabled Martí to infer the presence of a second binding site. “When the molecule is free in solution, its fluorescence has a specific lifetime due to this environment. However, when the molecule is attached to the amyloid fibers, the microenvironment is different and as a result that’s the life of the fluorescence,” he added. explained. “For the molecule bound to amyloid fibers, we observed two different fluorescence lifetimes.

“The molecule was only binding to a specific site in the amyloid-beta with two different sites. And that was very interesting because our previous studies only showed one binding site. That happened because we couldn’t to see all the components with the technologies we were using before,” he said.

The discovery prompted further experimentation. “We decided to look into this further using not only the probe we designed, but also other molecules that have been used for many years in inorganic photochemistry,” he said. “The idea was to find a negative control, a molecule that wouldn’t bind to amyloid-beta. But what we found was that these molecules that we didn’t expect would bind to amyloid-beta at all with reasonable affinity . . .

Martí said that the results 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 mechanisms of amyloid proteins is also useful for the study of non-pathogenic amyloids and their potential applications in drug development and materials science.

“There are functional amyloids that our body and other organisms produce for various reasons that are not related to disease,” said Martí. “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. another way that our results can be developed.”

More information:
Bo Jiang et al, Dissecting binding sites in amyloid nanofibrils using time-resolved spectroscopy, Chemical Science (2023). DOI: 10.1039/D2SC05418C

Available at Rice University

Quote: Research shows protein plaques associated with Alzheimer’s are stickier than thought (2023, January 25) retrieved January 25, 2023 from https://phys.org/news/2023-01-reveals-protein-plaques- alzheimer-stickier.html

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