PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations

Abstract

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...

Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling

“…Interestingly, our kinetic analysis reveals that PS1 becomes necessary for maintaining PI3K signaling during this developmental stage, suggesting that PS1 may be necessary for contact-dependent activation of neuronal PI3K/Akt signaling. This suggestion is supported by recent data that PS1 regulates the cadherindependent activation of PI3K (Baki et al, 2004;Uemura et al, 2007).…”

“…Thus, although contribution of other pathways cannot be excluded, our data show that PS1/PI3K/Akt signaling is both necessary and sufficient to suppress apoptosis and prevent neuronal degeneration. In accordance with previous studies showing that the ability of PS1 to activate PI3K/Akt signaling is independent of ␥-secterase activity (Baki et al, 2004;Kang et al, 2005), the survival effects of PS1 were not affected by ␥-secretase inhibitors. It should be noted that the PS1 homologous protein presenilin 2 (PS2) which has also been implicated in the regulation of PI3K/Akt signaling (Kang et al, 2005), is present in our PS1Ϫ/Ϫ cultures.…”

“…Over-activation of GSK-3 in response to PS1 FAD mutations has been reported in several cell culture systems (Weihl et Because GSK-3 is a major tau kinase (for review, see Kaytor and Orr, 2002;Bhat et al, 2004), it is expected that increased GSK-3 activity would result in increased phosphorylation of tau at GSK-3 target residues. Indeed, we and others have previously shown that presenilin suppresses tau phosphorylation via PI3K/ Akt/GSK-3 signaling (Baki et al, 2004;Kang et al, 2005) and that PS1 FAD mutants unable to inactivate GSK-3 fail to suppress GSK-3-dependent phosphorylation of exogenous tau (Baki et al, 2004). In primary neurons however, we observed no consistent difference between WT and mutant PS1 in terms of tau phosphorylation at GSK-3 target residues, although we did observe such a tendency in several of our experiments (data not shown).…”

“…Anti-GSK-3␤ antibody was from BD Biosciences (Franklin Lakes, NJ). Antibodies against the N-terminal and C-terminal fragments of PS1 (PS1/ NTF and PS1/CTF, respectively) have been described previously (Baki et al, 2004). ␥-secretase inhibitors (L-685,458 and compound E) were from Calbiochem (La Jolla, CA).…”

“…Presenilin1 (PS1) is a ubiquitously expressed transmembrane protein that plays critical roles in development (Shen et al, 1997;Wong et al, 1997) and in early onset familial Alzheimer's disease (FAD) (Sherrington et al, 1995). Recent studies in fibroblast cells implicate PS1 in the regulation of the PI3K/Akt signaling pathway (Baki et al, 2004;Kang et al, 2005;Uemura et al, 2007). Here we used primary neuronal cultures to investigate the role of PS1 and its FAD mutants in the neuronal PI3K signaling, as such studies may yield information on the mechanism by which PS1 FAD mutations promote neurodegeneration.…”