Presenilins Mediate Phosphatidylinositol 3-Kinase/AKT and ERK Activation via Select Signaling Receptors

Abstract

The Alzheimer's disease-linked genes, PS1 and PS2, are required for intramembrane proteolysis of multiple type I proteins, including Notch and amyloid precursor protein. In addition, it has been documented that PS1 positively regulates, whereas PS1 familial Alzheimer disease mutations suppress, phosphatidylinositol 3-kinase (PI3K)/Akt activation, a pathway known to inactivate glycogen synthase kinase-3 and reduce tau phosphorylation. In this study, we show that the loss of presenilins not only inhibits PI3K/Akt signaling and increases tau phosphorylation but also suppresses the MEK/ERK pathway. The deficits in Akt and ERK activation in cells deficient in both PS1 and PS2 (PS؊/؊) are evident after serum withdrawal and stimulation with fetal bovine serum or ligands of select receptor tyrosine kinases, platelet-derived growth factor receptor ␤ (PDGFR␤) and PDGFR␣, but not insulin-like growth factor-1R and epidermal growth factor receptor. The defects in PDGF signaling in PS؊/؊ cells are due to reduced expression of PDGF receptors. Whereas fetal bovine serum-induced Akt activation is reconstituted by both PS1 and PS2 in PS؊/؊ cells, PDGF signaling is selectively restored by PS2 but not PS1 and is dependent on the N-terminal fragment of PS2 but not ␥-secretase activity or the hydrophilic loop of PS2. The rescue of PDGF receptor expression and activation by PS2 is facilitated by FHL2, a PS2-interacting transcriptional co-activator. Finally, we present evidence that PS1 mutations interfere with this PS2-mediated activity by reducing PS2 fragments. These findings highlight important roles of both presenilins in Akt and ERK signaling via select signaling receptors.Mutations in two homologous presenilin genes, PS1 and PS2, account for the vast majority of early onset familial Alzheimer disease (FAD 1 ) (1, 2), whose pathology is virtually identical to sporadic AD characterized by deposition of A␤ and hyperphosphorylated tau inclusion in neurofibrillary tangles. The presenilins are polytopic proteins with 6 -8 transmembrane domains that are found in high molecular weight complexes together with nicastrin, pen-2, and aph-1. These four proteins are required for the regulated intramembrane proteolysis (RIP or ␥-secretase activity) of various substrates, including the amyloid precursor protein (APP) and Notch (3). Accordingly, null mice for any one of these components display embryonic lethality associated with severe malformations of the axial skeleton and cerebral hemorrhage, resembling that of Notch deficiency (3). As expected, this activity is conserved in Caenorhabditis elegans and Drosophila, where the presenilin complex functions to facilitate Notch signaling (4, 5). All presenilin mutations associated with FAD favor the enhanced production of the pathogenic A␤42 peptide, suggesting that this is the primary cause of familial cases of AD. Although the amyloid hypothesis is the leading model for AD pathogenesis, a number of concerns with this hypothesis have led many to suggest that non-amyloid-related cellular perturbati...

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

“…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.…”

“…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. Currently, it is unclear what the contribution of PS2 is in our system and whether absence of both presenilins would result in accelerated neuronal degeneration.…”

“…Our data, combined with those from previous studies on the role of WT and mutant presenilins on PI3K/Akt signaling (Weihl et al, 1999;Baki et al, 2004;Kang et al, 2005), suggest that this pathway may be downregulated in FAD. In agreement with this notion, decreased phosphorylation of Akt and increased GSK-3 activity were found in lymphoblasts derived from FAD patients carrying PS1 or PS2 mutations and in HEK293 cells expressing the Swedish APP FAD mutation (Ryder et al, 2004).…”

“…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).…”

“…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.…”