Light-Activated Probe Could Aid Alzheimer’s Drug Development

Researchers have developed a probe that lights up when it binds to a misfolded amyloid beta peptide (Aβ), enabling footprinting of this protein, which is a suspected cause of Alzheimer’s disease. The probe was able to identify a specific binding site on the Aβ, a discovery that could facilitate better drug treatment for the disease.

A rhenium-based complex developed at Rice University binds to fibrils of misfolded amyloid beta peptide, which marks the location of a hydrophobic cleft that could serve as a drug target, and oxidizes the fibril, which changes its chemistry in a way that could prevent further aggregation. Courtesy of Martí Group/Rice University.

When researchers at Rice University targeted Aβ fibrils using rhenium-based complexes, they found that photoirradiation of the complex caused oxidation on the Aβ fibril. Researchers used the photophysical and photochemical properties of this complex, as well as spectroscopic and computational methods, to elucidate the molecular binding sites on the Aβ fibrils. Tandem mass spectrometry analysis indicated where oxidation occurred, footprinting the place of binding, which was close to the site predicted by computer simulations.

“That oxidation only happens right next to the place where it binds,” said Rice researcher Angel Martí. “The real importance of this research is that it allows us to see with a high degree of certainty where molecules can interact with amyloid beta fibrils.”

A metallic probe lights up when it binds to a misfolded amyloid beta peptide in an experiment at Rice University. The probe identified a binding site that could facilitate better drugs to treat Alzheimer's disease. Courtesy of Brandon Martin/Rice University.

The study performed by the Rice team was backed up by computer simulations done by a team at the University of Miami (UM).

“The binding sites of the rhenium complex on fibrils were not known experimentally . . . Our computer modeling predicted binding sites and the modes of interactions of these molecules at the atomic level,” said UM researcher Rajeev Prabhakar.

The UM team predicted that the probe would attach itself to the peptide near a hydrophobic cleft that appeared on the surface of the fibril aggregate. According to researchers, this cleft represents a potential target for drugs.

“We believe this hydrophobic cleft is a general binding site (on amyloid beta) for molecules,” said Martí. “This is important because amyloid beta aggregation has been associated with the onset of Alzheimer's disease."

"There’s an interest in finding medications that will quench the deleterious effects of amyloid beta aggregates," Martí said. "But to create drugs for these, we first need to know how drugs or molecules in general can bind and interact with these fibrils, and this was not well-known. Now we have a better idea of what the molecule needs to interact with these fibrils.”

The discovery of the binding site, proposed in the UM lab and experimentally confirmed by the Rice lab, could lead to the development of photodynamic therapy for Alzheimer’s disease.

From left, Rice University research scientist Christopher Pennington, graduate student Bo Jiang and Angel Martí, an associate professor of chemistry and bioengineering, run an amyloid beta experiment in the Martí lab. Courtesy of Brandon Martin/Rice University.

“It’s a very attractive system because it uses light, which is a cheap resource,” Martí said. “If we can modify complexes so they absorb red light, which is transparent to tissue, we might be able to perform these photochemical modifications in living animals, and maybe some day in humans.

“We imagine it might be possible some day to prevent symptoms of Alzheimer’s by targeting amyloid beta in the same way we treat cholesterol in people now to prevent cardiovascular disease,” he said.

The research was published in Chem (doi: 10.1016/j.chempr.2017.09.011).

A probe invented at Rice University that lights up when it binds to a misfolded amyloid beta peptide — the kind suspected of causing Alzheimer's disease — has identified a specific binding site on the protein that could facilitate better drugs to treat the disease. Courtesy of Brandon Martin/Rice University.