Mapping the APP/presenilin (PS) binding domains: the hydrophilic N-terminus of PS2 is sufficient for interaction with APP and can displace APP/PS1 interaction.

Mutations in presenilin 1 and presenilin 2 (PS1 and PS2, respectively) genes cause the large majority of familial forms of early-onset Alzheimer's disease. The physical interaction between presenilins and APP has been recently described using coimmunoprecipitation. With a similar technique, we confirmed this interaction and have mapped the interaction domains on both PS2 and APP. Using several carboxy-terminal truncated forms of PS2, we demonstrated that the hydrophilic amino terminus of PS2 (residues 1 to 87, PS2NT) was sufficient for interaction with APP. Interestingly, only a construct with a leader peptide for secretion (SecPS2NT) and not its cytosolic counterpart was shown to interact with APP. For APP, we could demonstrate interaction of PS2 with the last 100 but not the last 45 amino acids of APP, including therefore the A beta region. Accordingly, SecPS2NT is capable of binding to A beta-immunoreactive species in conditioned medium. In addition, a second region in the extracellular domain of APP also interacted with PS2. Comparable results with PS1 indicate that the two presenilins share similar determinants of binding to APP. Confirming these results, SecPS2NT is able to inhibit PS1/APP interaction. Such a competition makes it unlikely that the PS/APP interaction results from nonspecific aggregation of PS in transfected cells. The physical interaction of presenilins with a region encompassing the A beta sequence of APP could be causally related to the misprocessing of APP and the production of A beta1-42.