Elucidation of the mechanism of action of Gamma Secretase Modulators

This project focuses on ultimately defining the structure of a soluble gamma-secretase modulator (SGSM)-bound gamma-secretase enzyme complex at high resolution. Defining the structure of this complex will provide critical information towards elucidating the mechanism of action of this promising series of therapeutic molecules known as SGSMs. This structural information will enable molecular dynamics simulations and can be used to identify critical sites of interaction between the SGSMs and their molecular target which we have shown to involve the catalytic subunit of the gamma-secretase enzymatic complex. These studies should enable a critical understanding of the mechanism of how these molecules selectively attenuate only the most pathogenic of the Abeta peptides, e.g., Abeta42 and could pave the way for identifying perhaps even more potent and more selective therapeutic agents for the treatment of Alzheimer’s disease.