The Alzheimer amyloid protein precursor (APP) has been shown to interact with phosphotyrosine-interacting domain (PID) containing proteins, including Fe65 and XI1. Both Fe65 and XI1 appear to function as adaptors, cross-linking APP with one or more additional proteins. Fe65 contains, in addition to the PID that binds APP, a second PED as well as a WW domain. XI1 contains, in addition to the PED that binds APP, two PDZ domains. It is of profound interest to determine what other proteins interact with Fe65 and XI1 to understand more about APP trafficking, localization and processing. We are making use of both the yeast two-hybrid system and biochemical methods to identify proteins interacting with Fe65 and XI1. For the yeast two-hybrid system we are using the WW domain of Fe65 and the PDZ domain of XI1. Recombinant PDZ domain of XI1 is also being used in biochemical assays for interacting proteins because of known difficulties with this domain in two-hybrid studies. Finally, we are also testing the hypothesis that the presenilins’ are able to bind PDZ-containing proteins, by determining whether the XI1 PDZ domain can interact with the presenilins