Presenilin 1 (PS1) plays important roles in development and in familial Alzheimer's disease (FAD). Cadherins are cell-cell adhesion receptors that control critical events in development and cell survival. The PI3K/Akt cell survival signaling is activated by growth factor receptors and promotes survival in almost all cell types including neurons, by downregulating the activity of pro-apoptotic factors and upregulating survival factors. Recent evidence however, shows that this pathway is also activated in response to cadherin-dependent cell adhesion and we showed that PS1 binds cadherins and promotes survival of confluent fibroblast cells by activating the cadherin/PI3K/Akt signaling. Confluent PS1 null (PS1-/-) fibroblasts display increased rates of apoptotic cell death, a phenotype rescued by exogenous PS1. PS1 promotes activation of PI3K/Akt signaling by stimulating the association of PI3K with cadherins. By activating this pathway, PS1 promotes phosphorylation/activation of Akt kinase while it downregulates the activities of both GSK-3 kinase and apoptotic caspase-3. This function of PS1 is independent of its role in gamma-secretase activity. Here we present data that survival of mature primary neuronal cultures depends on the ability of PS1 to activate the cadherin/PI3K/Akt signaling. Absence of PS1 activity at a developmental stage marked by formation of extensive neuronal contacts in vitro results in the inhibition of Akt and in the activation of both GSK-3 and apoptosis. Here we propose to examine the role of the PS1/cadherin/PI3K/Akt signaling in neuronal development and apoptosis and whether PS1 FAD mutants promote neuronal apoptosis and tau phosphorylation by interfering with this signaling. Since neuronal apoptosis and GSK-3 have been shown to increase Abeta production, we will examine the effects of the cadherin/PI3K/Akt signaling on Abeta. Finally, we will identify adaptor molecules promoting the PS1/cadherin/PI3K complex. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG008200-19
Application #
7150150
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Snyder, Stephen D
Project Start
1988-08-01
Project End
2011-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
19
Fiscal Year
2006
Total Cost
$344,626
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Huang, Qian; Voloudakis, Georgios; Ren, Yimin et al. (2018) Presenilin1/?-secretase protects neurons from glucose deprivation-induced death by regulating miR-212 and PEA15. FASEB J 32:243-253
Warren, Noel A; Voloudakis, Georgios; Yoon, Yonejung et al. (2018) The product of the ?-secretase processing of ephrinB2 regulates VE-cadherin complexes and angiogenesis. Cell Mol Life Sci 75:2813-2826
Nikolakopoulou, Angeliki M; Georgakopoulos, Anastasios; Robakis, Nikolaos K (2016) Presenilin 1 promotes trypsin-induced neuroprotection via the PAR2/ERK signaling pathway. Effects of presenilin 1 FAD mutations. Neurobiol Aging 42:41-9
Moreno, José L; Miranda-Azpiazu, Patricia; García-Bea, Aintzane et al. (2016) Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. Sci Signal 9:ra5
Zhu, Li; Zhong, Minghao; Elder, Gregory A et al. (2015) Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer's disease pathogenesis. Proc Natl Acad Sci U S A 112:11965-70
Bruban, Julien; Voloudakis, Georgios; Huang, Qian et al. (2015) Presenilin 1 is necessary for neuronal, but not glial, EGFR expression and neuroprotection via ?-secretase-independent transcriptional mechanisms. FASEB J 29:3702-12
Barthet, Gael; Dunys, Julie; Shao, Zhiping et al. (2013) Presenilin mediates neuroprotective functions of ephrinB and brain-derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors. Neurobiol Aging 34:499-510
Barthet, Gael; Georgakopoulos, Anastasios; Robakis, Nikolaos K (2012) Cellular mechanisms of ýý-secretase substrate selection, processing and toxicity. Prog Neurobiol 98:166-75
Georgakopoulos, Anastasios; Xu, Jindong; Xu, Chijie et al. (2011) Presenilin1/gamma-secretase promotes the EphB2-induced phosphorylation of ephrinB2 by regulating phosphoprotein associated with glycosphingolipid-enriched microdomains/Csk binding protein. FASEB J 25:3594-604
Xu, Jindong; Xilouri, Maria; Bruban, Julien et al. (2011) Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling. Neurobiol Aging 32:2326.e5-16

Showing the most recent 10 out of 66 publications