gamma-Secretase is an enzymatic complex, composed of presenilin 1 (PS1), 
nicastrin, pen-2, and aph-1, and is responsible for the intramembranous cleavage 
of various type-I membrane proteins. The level of each component is tightly 
regulated in a cell via proteasomal degradation. On the other hand, it has 
previously been reported that PS1/gamma-secretase is involved in the activation 
of phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway. PI3K is inhibited in 
Alzheimer's disease (AD) brain, whereas the effects of PI3K inhibition on the 
metabolism of PS1/gamma-secretase have not been elucidated. Here, we demonstrate 
that the treatment of neurons with PI3K inhibitors leads to increased levels of 
PS1/gamma-secretase components through an inhibitory effect on their 
degradation. Moreover, PI3K inhibition accelerated ubiquitination of PS1. We 
further show the evidence that the PS1 ubiquitination after PI3K inhibition is 
represented by the multiple mono-ubiquitination, instead of poly-ubiquitination. 
Accordingly, treatment of cells with PI3K inhibitor led to a differential 
intracellular redistribution of PS1 from the one observed after the proteasomal 
inhibition. These results suggest that PI3K inhibition may trigger the multiple 
mono-ubiquitination of PS1, which precludes the degradation of 
PS1/gamma-secretase through the proteasomal pathway. Since PS1/gamma-secretase 
is deeply involved in the production of Abeta protein, a deeper knowledge into 
its metabolism could contribute to a better elucidation of AD pathogenesis.