Research reveals protein plaques associated with Alzheimer’s are stickier than previously thought

Research reveals protein plaques associated with Alzheimer’s are stickier than previously thought

Scientists' discovery could lead to new therapies for Alzheimer's

A researcher in Rice’s Angel Marti 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 in amyloid beta deposits associated with Alzheimer’s disease, opening the door to the development of new therapies. Credit: Gustavo Raskosky/Rice University

Scientists at Rice University are using the lifetime of fluorescence 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 next few years. USA by 2060.

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

The study is published in chemistry.

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

“Understanding how molecules in general bind to amyloid beta is particularly important not only for developing drugs that bind with higher affinity to its aggregates, but also for discovering who the other players are that contribute to brain tissue toxicity.” added.

Scientists' discovery could lead to new therapies for Alzheimer's

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

Martí’s group had previously identified a first binding site for amyloid beta deposits by discovering how metal dye molecules could bind to pockets formed by fibrils. The ability of the molecules to fluoresce, or emit light when excited under a spectroscope, indicated the presence of the binding site.

Time-resolved spectroscopy, which the lab used in its latest discovery, “is an experimental technique that analyzes the time that molecules spend in an excited state,” Martí said. “We excite the molecule with light, the molecule absorbs the energy of the photons of light and goes to an excited state, a more energetic state.”

This energized state is responsible for the fluorescent glow. “We can measure the time that the molecules spend in an excited state, which is called lifetime, and then we use that information to assess the balance of binding of small molecules to beta-amyloid,” said Martí.

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

“These findings are allowing us to create a map of beta-amyloid binding sites and a record of the amino acid compositions required for the formation of binding pockets in beta-amyloid fibrils,” said Martí.

Scientists' discovery could lead to new therapies for Alzheimer's

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

The fact that time-resolved spectroscopy is sensitive to the environment surrounding the dye molecule allowed Martí to infer the presence of the second binding site. “When the molecule is free in solution, its fluorescence has a particular lifetime that is due to this environment. However, when the molecule is bound to amyloid fibers, the microenvironment is different and, as a consequence, so is the lifetime of fluorescence,” he said. explained. “For the molecule bound to amyloid fibers, we observed two different fluorescence lifetimes.

“The molecule was not binding to a single site on amyloid-beta but to two different sites. And that was extremely interesting because our previous studies only indicated one binding site. That happened because we couldn’t see all the components with the technologies that we were using previously,” he added.

The discovery sparked further experimentation. “We decided to investigate this further using not only the probe we designed, but also other molecules that have been used for decades in inorganic photochemistry,” he said. “The idea was to find a negative control, a molecule that didn’t bind beta-amyloid. But what we found was that these molecules that we didn’t expect to bind beta-amyloid actually did bind with decent affinity. ”

Martí said that the findings will also have an impact on the study of “many diseases associated with other types of amyloid: Parkinson’s, amyotrophic lateral sclerosis (ALS), type 2 diabetes, systemic amyloidosis.”

Understanding the binding mechanisms of amyloid proteins is also useful for studying 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 different reasons that are not associated with diseases,” 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. The study of non-pathogenic amyloids is an emerging area of ​​science, so that this is another path that our findings can help develop.”

More information:
Bo Jiang et al, Deconvoluting binding sites on amyloid nanofibrils using time-resolved spectroscopy, chemistry (2023). DOI: 10.1039/D2SC05418C

Provided by Rice University

Citation: Research Reveals Alzheimer’s-Associated Protein Plaques Are Stickier Than Thought (Jan 25, 2023) Accessed Jan 25, 2023 from reveals-protein-plaques-alzheimer-stickier.html

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