Treating the Cause, Not the Symptoms: Inhibition of Amyloid-β Protein Aggregation in Alzheimer's Disease

The cause of Alzheimer's disease (AD) has been associated with a buildup of protein plaques in and around brain cells, causing neurocellular death. One protein responsible for the buildup has been identified as the amyloid-ßprotein (Aß). Previous research has shown that the aggregation of Aß protein involves a series of structures: single monomer, partially aggregated soluble protofibrils and fully formed insoluble fibrils. Further research identified two distinct mechanisms by which soluble protofibrils progress to fibrils: elongation and association.

This project examined the inhibitory characteristics of a library of cyclic chemical compounds that could potentially inhibit Aß aggregation. Potential inhibitors were first scanned for their ability to inhibit fibril formation from monomer, without regard to growth mechanism. Effective inhibitors were then introduced into assays that isolate the elongation and association mechanisms of protofibril growth. Several bi-cyclic and tricyclic compounds were shown to selectively target protofibril association, while other compounds increased aggregation rates or had no effect. Inhibitor concentrations were then varied to examine dose dependence of inhibitors on Aß association. A neuronal cell model was then established in order to evaluate dose-response behavior of Aß induced toxicity.