Genetic analysis of familial Alzheimer's disease has revealed that mutations in 
the gamma-secretase enzyme presenilin promote toxic Abeta secretion; however, 
presenilin mutations might also influence tau hyperphosphorylation and 
neurodegeneration through gamma-secretase-independent mechanisms. To address 
this possibility and determine whether other components of the gamma-secretase 
complex possess similar regulatory functions, we analyzed the roles of 
presenilin, nicastrin, and aph-1 in a Drosophila model for tau-induced 
neurodegeneration. Here, we show that presenilin and nicastrin prevent tau 
toxicity by modulating the PI3K/Akt/GSK3beta phosphorylation pathway, whereas 
aph-1 regulates aPKC/PAR-1 activities. Moreover, we found that these 
transmembrane proteins differentially regulate the intracellular localization of 
GSK3beta and aPKC at cell junctions. Inhibition of gamma-secretase activity 
neither interfered with these kinase pathways nor induced aberrant tau 
phosphorylation. These results establish new in vivo molecular functions for the 
three components of the gamma-secretase complex and reveal a different mechanism 
that might contribute to neuronal degeneration in Alzheimer's disease.