Rab6 membrane association is dependent of Presenilin 1 and cellular phosphorylation events

Processing of the amyloid precursor protein (APP) by alpha-secretase precludes the formation of beta-amyloid (Abeta). Therefore, the increase of cleavage by a-secretase upon stimulation by protein kinase C (PKC) is of potential therapeutic interest for Alzheimer's disease (AD). Unknown is whether phosphorylation by PKC increases alpha-secretase-mediated cleavage directly or indirectly, for example, by modulation of APP trafficking. Because modulation of Rab6-mediated transport has been shown to affect APP processing, we investigated the regulation of Rab6 membrane association by PKC and its relation to PSI. We show that in fibroblasts, Rab6 membrane association is PKC dependent, an effect strongly potentiated by inhibition of calcineurin. Moreover, we demonstrate that this regulation of Rab6 membrane association is dependent on PSI. The possible implications for APP processing and AD are discussed. (C) 2004 Elsevier B.V. All rights reserved.