Princeton University set its sights on preventing amyloid-beta plaque, the most notorious culprit behind Alzheimer's. Using a revolutionary high-volume testing technique, learn about their success with D737.
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.
Princeton University researchers used a high-throughput — meaning many materials can be examined at once — screening process developed at Princeton to discover an organic compound that prevented the formation of protein clumps found on human brain cells afflicted by Alzheimer's disease. Fruit flies bred to exhibit Alzheimer's-like symptoms maintained their climbing ability after receiving the compound — called D737 — for two weeks (left), whereas flies that did not (right) get treatment exhibited the disorientation and loss of mobility associated with Alzheimer's. (Video courtesy of Angela Fortner McKoy)
The D737 compound worked by stopping the accumulation of a peptide known as amyloid beta 42 (Aβ42), which is thought to initiate the neural deterioration characteristic of Alzheimer's disease. The compound was tested on flies with a regular human Aβ42 gene (top graph) and flies with a mutant gene that causes extra buildup of the peptide (bottom graph). For each group, flies received none of the compound (black line), or concentrations of 2, 20 or 200 micromolar (blue, grey and red lines, respectively). Flies — particularly those with the mutant gene — survived longer when administered the compound. (Image courtesy of Angela Fortner McKoy)
Flies bred to express the Alzheimer's peptide Aβ42 maintained their climbing ability longer after receiving the D737 compound (black bars) than flies that did not receive the compound (gray bars). The top panel shows flies with the standard Aβ42 gene, while the bottom panel shows flies with a disease-causing mutant gene. (Image courtesy of Angela Fortner McKoy)