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  • Molecules 'Light Up' Alzheimer's Roots
Jul 2011
HOUSTON, July 14, 2011 — A breakthrough in sensing at Rice University could make finding signs of Alzheimer's disease nearly as simple as switching on a light, and should help bring about better medications to treat the devastating disease.

The lab of bioengineer Angel Martí is testing metallic molecules that naturally attach themselves to a collection of beta amyloid proteins, called fibrils, that form plaques in the brains of Alzheimer's sufferers. When the molecules, complexes of dipyridophenazine ruthenium, latch onto amyloid fibrils, their photoluminescence increases 50-fold.

Because of their increased fluorescence, these molecules could become an alternative to the molecules currently used to study amyloid fibrils, which researchers believe form when misfolded proteins begin to aggregate. Researchers use changes in fluorescence to characterize the protein transition from disordered monomers to aggregated structures.

Amyloid fibrils like those magnified here 12,000 times are thought to be the cause of plaques in the brains of Alzheimer's disease patients. Rice University researchers have created a metallic molecule that becomes strongly photoluminescent when it attaches to fibrils. (Image: Nathan Cook, Rice University)

Graduate student Nathan Cook, a former high school teacher, is the lead author of the Journal of the American Chemical Society paper reporting the technique. He began studying beta amyloids when he joined Martí's lab after taking a Nanotechnology for Teachers course taught by professor of chemistry John Hutchinson. Cook's goal was to find a way to dissolve amyloid fibrils in Alzheimer's patients. But the researcher realized that the ruthenium complexes, the subject of much study in Martí's group, had a distinctive ability to luminesce when combined in a solution with amyloid fibrils.

Such fibrils are simple to make in the lab, Cook said. Molecules of beta amyloid naturally aggregate in a solution, as they appear to do in the brain. Ruthenium-based molecules added to the amyloid monomers do not fluoresce, he said. But once the amyloids begin to aggregate into fibrils that resemble "microscopic strands of spaghetti," hydrophobic parts of the metal complex are naturally drawn to them.

"The microenvironment around the aggregated peptide changes and flips the switch" that allows the metallic complexes to light up when excited by a spectroscope, he said.

Thioflavin T (ThT) dyes are the standard sensors for detecting amyloid fibrils and work much the same way, Martí said. But ThT has a disadvantage because it fluoresces when excited at 440 nm and emits light at 480 nm – a 40-nm window.

That gap between excitation and emission wavelengths is known as the Stokes shift. "In the case of our metal complexes, the Stokes is 180 nm," said Martí, an assistant professor of chemistry and bioengineering. "We excite at 440 and detect in almost the near-infrared range, at 620 nm.

"That's an advantage when we want to screen drugs to retard the growth of amyloid fibrils," he said. "Some of these drugs are also fluorescent and can obscure the fluorescence of ThT, making assays unreliable."

Cook also exploited the material’s long-lived fluorescence by "time gating" spectroscopic assays. "We specifically took the values only from 300 to 700 ns after excitation," he said. "At that point, all of the fluorescent media have pretty much disappeared, except for ours. The exciting part of this experiment is that traditional probes primarily measure fluorescence in two dimensions: intensity and wavelength. We have demonstrated that we can add a third dimension — time — to enhance the resolution of a fluorescent assay."

The researchers said their complexes could be fitting partners in fluorescence lifetime imaging microscopy (FLIM), which discriminates microenvironments based on the length of a particle's fluorescence rather than its wavelength.

Cook's goal remains the same: to treat Alzheimer's — and possibly diseases such as Parkinson's — through the technique. He sees a path forward that may combine the ruthenium complex's ability to target fibrils with other molecules’ potential to dissolve them in the brain.

"That's something we are actively trying to target," Martí said.

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