New Rice University research approach sheds light on Alzheimer's disease research

A team of researchers from Rice University has used fluorescence lifetime (FLT) to understand a peptide associated with Alzheimer's disease, finding that protein plaques associated with disease are stickier than previously thought.

The research team, led by Angel Martí, used time-resolved spectroscopy and computational chemistry to uncover experimental evidence of an alternative binding site on amyloid-beta aggregates, according to a Rice University news release. It is a breakthrough that could ultimately led to the development of new therapeutic options for Alzheimer’s and other diseases that are connected to amyloid deposits. The Centers for Disease Control and Prevention estimates that approximately 14 million people in the United States will be affected by Alzheimer's by 2060.

“Amyloid-beta is a peptide that aggregates in the brains of people that suffer from Alzheimer’s disease, forming these supramolecular nanoscale fibers, or fibrils,” Martí; a professor of chemistry, bioengineering, and materials science and nanoengineering and faculty director of the Rice Emerging Scholars Program; said in the news release. “Once they grow sufficiently, these fibrils precipitate and form what we call amyloid plaques.”

Martí explained that understanding how molecules bind to amyloid-beta is key to unlocking new therapeutics that can attach themselves to amyloid aggregates and also for detecting contributing factors to cerebral tissue toxicity.

“Understanding how molecules in general bind to amyloid-beta is particularly important not only for developing drugs that will bind with better affinity to its aggregates, but also for figuring out who the other players are that contribute to cerebral tissue toxicity,” Martí said in the release.

In a previous study, Martí’s group detected a key binding site for the amyloid-beta deposits by examining the way the molecules might bind to pockets within the fibrils as well as the ability to fluoresce under spectroscopy, highlighting a binding site.

The team’s latest research used time-resolved spectroscopy to determine the time molecules spend in an excited state, according to the news release. They witnessed the time the molecules spent in the excited state, termed as lifetime, and were able to determine the binding equilibrium of small molecules to amyloid-beta.

The team, working with the University of Miami, learned that multiple fluorescent dyes could bind to amyloid deposits, something that was not initially expected to happen. This is key to the development of a binding site map in amyloid-beta and a record of the amino acid compositions necessary for the development of binding pockets in amyloid-beta fibrils.

Martí pointed out that the sensitivity of time-resolved spectroscopy to its environment of the dye molecule enabled scientists to determine the presence of another binding site, the release said.

The researchers also noted that the FTL of the molecule was different when it was linked to amyloid fibers compared to when it was in the solution free of connection. Through additional research, the team found that molecules that were not expected to bind to amyloid-beta would show a positive ability to bind.

In addition to Alzheimer’s disease research, Martí said the discovery could impact work in diseases linked with a range of amyloids, including Parkinson's, amyotrophic lateral sclerosis (ALS), Type 2 diabetes and systemic amyloidosis; according to the release. Additionally, uncovering the mechanisms for binding of amyloid proteins could prove to be valuable in the study of nonpathogenic amyloids.

The research was supported by the National Science Foundation and the family of the late Donald DuPré, a Rice alumnus and former chemistry professor at the University of Louisville, the release said.