Amyloid protein plaques, particularly ones made of beta-amyloid 42, are a prime suspect in the development of Alzheimer’s disease. Soluble oligomers, in this case molecules with a few repeating peptide units, may turn out to be the main culprit. They’re known to be toxic to neurons and some recent studies have led researchers to focus more attention on them.
To better understand the root causes of Alzheimer’s, researchers need a way to track oligomers in the lab, but Thioflavin T dyes that lab techs use to flag amyloid fibrils don’t work well with oligomers. To overcome this serious limitation, chemists at Rice University have now synthesized fluorescent ruthenium-based tags that attach themselves to oligomeric amyloid beta peptides during their formation.
The tagging allows scientists to follow the growth and movement of the aggregates, and will hopefully lead to a better understanding of the development of Alzheimer’s disease.
“There’s a view in the field that soluble oligomers are the main cause of neuronal degeneration, because these oligomers are toxic to neurons,” said Angel Martí, a professor at Rice and the lead researcher of the study appearing in Journal of the American Chemical Society. “These oligomers are definitely associated with Alzheimer’s pathology, so there’s been a need for tools to help us study them.”
The new molecular tags rely on fluorescence anisotropy, a phenomenon that results in polarized fluorescence, making the molecules look brighter from some angles than others. In a solution, molecules move freely and rotate. The smaller the molecule, the faster it can spin, but when it attaches to a larger molecule the observed rotation becomes significantly slower.
When the ruthenium-based tags bind to oligomers, the twinkling caused by their polarization slows down, pointing to the presence of the target oligomers.
The new tags won’t answer all questions, though, because they cannot be used inside the brain because of the high scattering of light caused by brain tissue, especially polarized light. Nevertheless, in lab studies the Rice researchers have already shown that oligomers form exceedingly well at body temperatures and that they are highly toxic to neuroblastoma cells while amyloid fibrils and monomers don’t seem to do as much damage.
Certainly the new tags will be an important tool to better understand Alzheimer’s and find a cure for this mysterious disease.
Study in Journal of the American Chemical Society: Monitoring the Formation of Amyloid Oligomers Using Photoluminescence Anisotropy