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

0

A researcher in Rice’s Angel Martí’s lab holds a vial of fluorescent dye molecules in solution. Using time-resolved spectroscopy, which tracks the fluorescence lifetime of dye molecules, Martí and collaborators 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 use fluorescence lifetime to shed new light on a peptide linked to Alzheimer’s disease, which the Centers for Disease Control and Prevention estimates will affect nearly 14 million people in the U.S. by 2060 .


Taking a novel approach using time-resolved spectroscopy and computational chemistry, Angel Martí and his team found experimental evidence of an alternative binding site on amyloid-beta aggregates, opening the door to the development of new therapies for Alzheimer’s and other diseases related to amyloid deposits. .

The study is published in Chemical Science.

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

“Understanding how molecules in general bind to amyloid beta is especially important, not only for developing drugs that bind to its aggregates with better affinity, but also for finding out who the other players are that contribute to cerebral tissue toxicity. ,” he added.

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

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

The Martí group had previously identified a first binding site for amyloid-beta deposits by figuring out how metal dye molecules could bind to cavities formed by the 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 looks at the time molecules spend in an excited state,” Martí said. “We excite the molecule with light. The molecule absorbs the energy of the light photons and enters an excited state, a more energetic state.”

This energetic state is responsible for the fluorescent glow. “We can measure the time molecules spend in the excited state, which is called lifespan, and then use that information to evaluate the binding equilibrium of small molecules to amyloid beta,” Martí said.

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

“These findings allow us to map binding sites in amyloid-beta and outline the amino acid compositions required for binding pocket formation in amyloid-beta fibrils,” Martí said.

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

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

The fact that time-resolved spectroscopy is sensitive to the environment around the dye molecule enabled Martí to deduce the presence of the second binding site. “When the molecule is free in solution, the fluorescence has a certain lifetime due to this environment. However, when the molecule is bound to the amyloid fibers, the microenvironment is different and, as a result, so does the lifetime of the fluorescence ,” he explained. “For the molecule bound to amyloid fibers, we observed two different fluorescence lifetimes.

“The molecule did not bind to a unique site in the 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 we used before,” he added.

The discovery led to more experiments. “We decided to investigate this further, not only using 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 wouldn’t bind to amyloid beta. But what we found was that these molecules that we didn’t expect to bind to amyloid beta in the first place did, in fact, bind with decent affinity to unions.”

Martí said the findings will also impact the study of “many diseases related to 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 studying non-pathogenic 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 associated with disease,” Martí 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 non-pathogenic amyloids is an emerging field of science, so this is another pathway that our findings may help develop.”

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

Offered by Rice University

Quote: Study 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- sticker.html

This document is copyright protected. Other than fair dealing for private study or research, nothing may be reproduced without written permission. The content is provided for informational purposes only.

Leave A Reply

Your email address will not be published.