title: gamma-cleavage-independent functions of presenilin, nicastrin, and Aph-1 regulate cell-junction organization and prevent tau toxicity in vivo.
abstract: 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.
authors: Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, 10043, Orbassano, Torino, Italy.
authors: Laura E
authors: LE
authors: Doglio
authors: Ritu
authors: R
authors: Kanwar
authors: George R
authors: GR
authors: Jackson
authors: Mar
authors: M
authors: Perez
authors: Jesús
authors: J
authors: Avila
authors: Colin
authors: C
authors: Dingwall
authors: Carlos G
authors: CG
authors: Dotti
authors: Mark E
authors: ME
authors: Fortini
authors: Fabián
authors: F
authors: Feiguin