Role of the Presenilin1mediated Cleavage of E-cadherin

Mutations in presenilin-1 (PS1) are responsible for familial Alzheimer’s disease (FAD), also known as early-onset Alzheimer’s disease. PS1 is found at the plasma membrane and is involved in cell-cell contacts. It interacts with E-cadherin, a cell surface molecule that facilitates cell-cell adhesions and has a crucial role in the structure of the synapse, the region involved in neuron communication. E-cadherin forms complexes with cytosolic proteins, like catenins, to link the actin cytoskeleton. The remodeling of cell-cell interactions is a central determinant for many functions, including tissue repair, cell migration and cell death. The molecular mechanisms involved in the disassembly of cell-cell associations are not clearly understood. It has been shown E-cadherin processing is mediated by PS1/gamma secretase activity. Dr. Marambaude is investigating whether PS1-mediated cleavage of E-cadherin disconnects the cadherin with the cytoskeleton and plays a role in the disassembly of cell-cell adhesions. He also plans to study the signaling pathways that are activated by the PS1/gamma secretase-mediated processing of E-cadherin and the subsequent disassembly of cadherin/catenin complexes. Finally, he will examine whether mutated PS1 in FAD abnormally affects its activity to cleave E-cadherin and thereby participating in the neuronal loss observed in Alzheimer’s disease. This project will help to determine the usefulness of treatments using gamma-secretase inhibitors in altering the E-cadherin-dependent adhesion and signaling systems.