Molecular Dissection of the Gamma Secretase Complex

The neuropathological hallmark of Alzheimer’s disease (AD) is the presence of senile plaques throughout the cortex and hippocampus of affected individuals. Senile plaques are composed of extracellular deposits of a small peptide, termed beta-amyloid, or Aß. Aß is derived through the processing of a protein referred to as amyloid precursor protein (APP). There is evidence to suggest that the gene Presenilin 1 (PS1) is present as a complex with several additional membrane proteins, termed NCT, APH-1, and PEN-2. It is believed that these proteins are components of a complex required for “γ-secretase” activity, which leads to the release of the peptide from APP. However, the structural components that govern the interactions of this complex are not well understood. Dr. Sisodia has developed a model system in the yeast, Pichia pastoris, to provide a description of the structural determinants that promote the assembly of PS1, nicastrin (NCT), APH-1 and PEN-2, and to understand the order of the association of the components. This model will allow Dr. Sisodia to examine the interaction of these components and to define the minimal structural components required for the assembly of the complex. The information gained from this project could lay the groundwork for the development of new treatments that target γ-secretase and inhibit Aß production in the brain.