D737 compound restores motor function and longevity in fruit flies with Alzheimer's

Published on November 16, 2012 at 3:27 AM · No Comments

An efficient, high-volume technique for testing potential drug treatments for Alzheimer's disease uncovered an organic compound that restored motor function and longevity to fruit flies with the disease, according to new research that could help put the search for an effective Alzheimer's drug on a faster track.

Princeton University researchers report in the Journal of Biological Chemistry that they discovered an organic compound that prevented the formation of protein clumps, or aggregates, found on human brain cells afflicted by Alzheimer's disease. The researchers realized the compound's potential via a high-throughput - meaning many materials can be examined at once - screening process developed at Princeton that examined the ability of 65,000 molecular compounds to inhibit protein aggregation.

When administered to fruit flies bred to exhibit Alzheimer's-like symptoms, the compound - which the researchers call D737 - restored climbing ability and increased the flies' lifespan by several days in comparison to flies that did not receive the compound, the researchers reported.

The compound worked by stopping the accumulation of a peptide known as amyloid beta 42 (Aβ42), which disrupts cell function, is found in high quantities in Alzheimer's plaques, and is thought to initiate the disease's characteristic neural deterioration. The fruit flies were genetically engineered at the University of Cambridge to have human Aβ42 collect in their neurons. As in humans, this accumulation results in memory and mobility loss, disorientation and early death.

Senior researcher Michael Hecht, a Princeton professor of chemistry, said the findings demonstrate a quick and efficient screening method that could help in the search for a medicinal defense against Alzheimer's. Currently, he said, the disease's proliferation in an aging population has outpaced the success of efforts todevelop a treatment for it.

"As the population ages, Alzheimer's is the big disease," Hecht said. "There are drugs to control symptoms, but nothing to treat the disease itself. One approach could be to control peptide aggregation as we have done, but the compounds tested so far often fail.

"Our technique would allow scientists to create an artificial genetic system, examine it with a high-throughput screen and find whether it works," Hecht said. "From that they can fish out the best results and test them in other models."

Furthermore, an effective compound such as D737 can reveal information about Aβ42's structure that can be used to formulate other treatments, said lead author Angela Fortner McKoy, a postdoctoral researcher at Rutgers University who received her Ph.D. in chemistry from Princeton in 2011. Fortner McKoy and Hecht worked with second author Jermont Chen, who earned his Ph.D. in chemistry from Princeton in 2008, andTrudi Sch-pbach, the Henry Fairfield Osborn Professor of Biology.

The Princeton researchers used a screening process developed in the Hecht lab to specifically identify Aβ42 aggregation. First reported in the journal ACS Chemical Biology in 2006, the technique hinges on a fusion of Aβ42 and green fluorescent protein - which glows under ultraviolet light and is found in animals such as jellyfish - that is expressed in the bacteria E. coli. The fluorescent protein does not glow when Aβ42 is able to aggregate. When a compound such as D737 inhibits peptide clumping, however, the E. coli bacterium appears bright green. The efficiency of the screening system stems from the relative simplicity of attaining andworking with E. coli, a standard laboratory bacterium, Hecht said.

For the current research, Hecht and his co-authors examined 65,000 randomly chosen organic compounds that Chen acquired from the Broad Institute of the Massachusetts Institute of Technology and Harvard University. The technique revealed 269 compounds that halted the buildup of Aβ42 aggregates. Of those, Fortner McKoy selected the eight most readily available for further testing. Fortner McKoy found that D737 best prevented the accumulation of Aβ42 and reduced mortality in cell cultures. In addition, the researchers found that the compound reduced the production and accumulation of reactive oxygen species, which damage cells.

The researchers then tested the compound on healthy fruit flies with no Aβ42 accumulation, as well as on flies with a regular human-form Aβ42 gene and flies with a mutant gene - which is found in some humans with Alzheimer's - that causes extra buildup of the peptide. For each of these three fly types, one group of flies did not receive D737 while another group was given the compound in concentrations of 2, 20 or 200 micromolar.

In the flies with regular and accelerated Aβ42 buildup, those receiving D737 lived an average of four to six days longer than similarly altered flies that were not fed the compound. The healthy fruit flies that received D737 showed no change in lifespan, demonstrating that the compound is non-toxic in fruit flies, Hecht said.

To test mobility, the researchers put 20 flies from both of the genetically altered groups into the bottom of a vial and recorded how many had climbed to the top. After 38 days, only 6 percent of untreated flies with normal Aβ42 accumulation could climb, as opposed to as many as 34 percent of the flies receiving D737.

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