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) gene s cause the large majority of familial forms of early-onset Alzheimer's dis ease. The physical interaction between presenilins and APP has been recentl y described using coimmunoprecipitation. With a similar technique, we confi rmed this interaction and have mapped the interaction domains on both PS2 a nd APP. Using several carboxy-terminal truncated forms of PS2, we demonstra ted that the hydrophilic amino terminus of PS2 (residues 1 to 87, PS2NT) wa s sufficient for interaction with APP. Interestingly, only a construct with a leader peptide for secretion (SecPS2NT) and not its cytosolic counterpar t 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 AP region. Accordingly, SecPS2NT is capable of binding to A beta-immunoreactive species in conditioned medium. In addition, a second re gion in the extracellular domain of APP also interacted with PS2. Comparabl e results with PS1 indicate that the two presenilins share similar determin ants of binding to APP. Confirming these results, SecPS2NT is able to inhib it PS1/APP interaction. Such a competition makes it unlikely that the PS/AP P interaction results from nonspecific aggregation of PS in transfected cel ls. The physical interaction of presenilins with a region encompassing the A beta sequence of APP could be causally related to the misprocessing of AP P and the production of A beta 1-42. (C) 1999 Academic Press.