Phosphatidylinositol 3-kinase (PI3K) promotes cell survival and communication by activating its downstream effector Akt kinase. Here we show that PS1, a protein involved in familial Alzheimer's disease (FAD), promotes cell survival by activating the PI3K/Akt cell survival signaling. This function of PS1 is unaffected by c-secretase inhibitors. Pharmacological and genetic evidence indicates that PS1 acts upstream of Akt, at or before PI3K kinase. PS1 forms complexes with the p85 subunit of PI3K and promotes cadherin/PI3K association. Furthermore, conditions that inhibit this association prevent the PS1-induced PI3K/Akt activation, indicating that PS1 stimulates PI3K/Akt signaling by promoting cadherin/PI3K association. By activating PI3K/Akt signaling, PS1 promotes phosphorylation/inactivation of glycogen synthase kinase-3 (GSK-3), suppresses GSK-3-dependent phosphorylation of tau at residues overphosphorylated in AD and prevents apoptosis of confluent cells. PS1 FAD mutations inhibit the PS1-dependent PI3K/Akt activation, thus promoting GSK-3 activity and tau overphosphorylation at ADrelated residues. Our data raise the possibility that PS1 may prevent development of AD pathology by activating the PI3K/Akt signaling pathway. In contrast, FAD mutations may promote AD pathology by inhibiting this pathway.
IntroductionIncreased neuronal cell death, tau overphosphorylation and accumulation of neurofibrillary tangles (NFTs) and amyloid plaques are the main pathological hallmarks of Alzheimer's disease (AD) brains. The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays crucial roles in the transmission of survival signals in a wide range of cell types including neurons (for reviews, see Chan et al, 1999;Brunet et al, 2001). PI3K activates its downstream effector Akt/protein kinase B (Akt) by promoting its phosphorylation at residues serine 473 (Ser473) and threonine 308 (Thr308). Activated Akt, in turn, phosphorylates a wide range of substrates activating anti-apoptotic (survival) factors and inactivating pro-apoptotic factors (Brunet et al, 2001). The PI3K/Akt pathway is activated following recruitment of PI3K to the plasma membrane in response to a number of extracellular stimuli including growth factors (Brunet et al, 2001) and cadherin homophilic cell-cell adhesions, which result in the recruitment of PI3K to adhesion complexes (Pece et al, 1999;Kovacs et al, 2002;Tran et al, 2002;Yap and Kovacs, 2003). Akt downregulates the activities of glycogen synthase kinases 3a (GSK-3a) and 3b (GSK-3b) by phosphorylating the former at residue serine 21 (Ser21) and the latter at residue serine 9 (Ser9) (Cross et al, 1995;Kaytor and Orr, 2002). Increased GSK-3b activity has been implicated in neuronal cell death (Pap and Cooper, 1998;Hetman et al, 2000;Cross et al, 2001;Lucas et al, 2001) and tau overphosphorylation (Hanger et al, 1992;Hong et al, 1997;Pei et al, 1999;Lucas et al, 2001), while GSK-3a was recently implicated in the production of Ab peptide, the principal protein component of amyloid plaques (Phiel et...