Effects of PS1 deficiency on membrane protein trafficking in neurons

We have examined the trafficking and metabolism of the beta-amyloid precurs or protein (APP), an APP homolog (APLP1), and TrkB in neurons that lack PS1 . We report that PS1-deficient neurons fail to secrete A beta, and that the rate of appearance of soluble APP derivatives in the conditioned medium is increased. Remarkably, carboxyl-terminal fragments (CTFs) derived from APP and APLP1 accumulate in PS1-deficient neurons. Hence, PS1 plays a role in promoting intramembrane cleavage and/or degradation of membrane-bound CTFs. Moreover, the maturation of TrkB and BDNF-inducible TrkB autophosphorylati on is severely compromised in neurons lacking PS1. We conclude that PS1 pla ys an essential role in modulating trafficking and metabolism of a selected set of membrane and secretory proteins in neurons.