Probes bring new light on the cause of Alzheimer's

Researchers at Rice University have found a way to track the formation of aggregates of soluble beta-amyloid peptides involved in the onset of Alzheimer's disease.

Angel Martí's rice lab has announced that it has developed a ruthenium-based fluorescent complex that binds soluble oligomeric beta-amyloid peptides. When peptides come together to form large biomolecules called oligomers, the fluorescent additive binds them and marks them.

This will allow researchers to easily track the progress and movements of aggregates over time. The details of the work appear in the Journal of the American Chemical Society.

Amyloid plaques have long been suspected of being at the origin of Alzheimer's disease, but recent studies suggest that oligomers – floating molecules with repeating peptide units – cause much more damage.

"Some believe in the field that soluble oligomers are the main cause of neuronal degeneration because they are toxic to neurons," said Martí, an associate professor of chemistry, bioengineering, materials science and nanoscale engineering.

"These oligomers are clearly associated with Alzheimer's pathology, so we need tools to help us study them."

He added that oligomers are "virtually invisible" to Thioflavin T dyes commonly used to label amyloid fibrils in laboratory studies. Ruthenium complexes solve this problem.

The complexes take advantage of the anisotropy of fluorescence, in which the fluorescence response is polarized and becomes brighter in some directions than in others. "It's a very old technique related to the rotation of molecules," said Martí. "When the molecule is in solution, it moves and rotates constantly.When it is very small, it turns very fast and the anisotropy is almost nil.

"But when the same probe binds to a big macromolecule, it runs slower," he said. "That's how we know we have oligomers and then we can track their growth and spread."

Laboratory tests showed that oligomers formed in solution at different temperatures within a few hours. Martí noted that cold solutions slow down the process, but that at body temperature, oligomers form "very rapidly and in large quantities, and the rate at which they form at physiological temperatures is remarkable."

Rice also used its probes to see how neuroblastoma cells were affected in real time when amyloid beta-peptides were injected. They revealed that only 60% of the cells injected with oligomers remained viable, while those treated with amyloid fibrils and monomers had a higher viability, about 80%, suggesting that the oligomers are actually toxic, said Martí. .

For the moment, he said, the ruthenium probes are intended to be used only in the laboratory. "It will be difficult to use them in the brain because there is too much scattering of light," said Martí. "They are designed to take advantage of polarized light, and diffusion would mitigate it."

"But as a laboratory tool, they will allow researchers around the world to test the effects of other molecules on the rate of oligomer formation, which is a big deal," she said. he declared. "They can quickly see if a drug delays or stops the formation of oligomers."