The presenilins have been implicated in both AB formation and in apoptosis. Studies of apoptosis implicate the COOH-terminal -100 amino acids of the presenilins in this process. Moreover, evidence suggests that these effects of the presenilins involve protein-protein interactions. Recently, it has also been shown that the COOH-terminal -5 amino acids of presenilin-2 are responsible for the effects of the FAD mutations on A842 formation. Taken together, these studies support research aimed at the identification of proteins that interact with the COOH-terminus of the presenilins. We are making use of the yeast two-hybrid system to identify proteins that interact with the COOH-terminus of the presenilins. While screening a human brain library, we have identified the novel calcium and presenilin-binding protein calsenilin as an interactor and we are currently studying its role in both apoptosis and in AB formation. More recently, we have carried out a two-hybrid screen in a rat brain library to identify additional interactors. We have identified three classes of interacting clones that are being characterized for localization and for interaction in mammalian cells. These interactors are also being characterized for their role in apoptosis and in AB formation. Finally, we are studying whether proteins already implicated in APP processing are able to interact with the COOH-terminus of the presenilins