A screen for molecules that inhibit formation of A-beta oligomers in yeast

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DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurological disorder that effects large numbers of elderly people. It is characterized by the formation of plaques in the brain that are largely composed of SDS resistant fibrils of beta-amyloid peptide (A-beta). A considerable body of evidence supports the amyloid cascade hypothesis that proposes that accumulation of A-beta peptide triggers the appearance of AD. While early evidence indicated that the A-beta amyloid fibrils are neuro-toxic, recent research points to the SDS stable oligomers (that have been detected both in vivo and in vitro) as the primary neuro-toxic species. One promising emerging approach for the treatment of AD is to prevent these oligomers from forming. Indeed, disruption of these oligomers rather than the larger fibrils seems prudent since inhibition of A-beta fibril formation might cause the harmful oligomer species to accumulate and since inhibiting oligomer formation should also prevent the initial formation of the fibrils. Currently there are no simple assays for oligomer formation that would allow a direct screen for such drugs. We are developing a yeast model system of A-beta oligomerization to provide an assay that will facilitate such a direct drug screen. The system employs a fusion of A-beta to the yeast translational release factor (RF). The RF reporter will only be active and allow cells to grow on test media if the fusion does not oligomerize. Using this model system, we will develop a high throughput assay that will allow us to screen for small molecules that inhibit the A-beta dependent oligomerization of the translational release factor. Our goal is to create an assay that allows us to detect disruption of the oligomerization stage of A-beta aggregation by simply selecting for small molecules that permit or inhibit growth on test media. Eventually by looking at the structure of the molecules active in our assay it will be possible to design compounds that enhance their ability to block A-beta oligomerization and to work as a drug in humans to treat or prevent Alzheimer's disease. Finally, animal and human trials would be required.