Abstract

The aggregation of the 42-residue form of the amyloid-beta peptide (Abeta42) is a pivotal event in Alzheimer’s disease (AD). The use of chemical kinetics has recently enabled highly accurate quantifications of the effects of small molecules on specific microscopic steps in Abeta42 aggregation. I will explain how we have exploited this approach to develop a rational drug discovery strategy against Abeta42 aggregation that uses as a read-out the changes in the nucleation and elongation rate constants caused by candidate small molecules. We have thus identified a pool of compounds that target specific microscopic steps in Abeta42 aggregation. We have then tested further these small molecules in human cerebrospinal fluid and in a Caenorhabditis elegans model of AD. These results show that this strategy represents a powerful approach to identify systematically small molecule lead compounds, thus offering an appealing opportunity to reduce the attrition problem in drug discovery.