Cadherin/PS1/P123K/Akt signaling in neuronal survival and AD

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

[unreadable] DESCRIPTION (provided by applicant): 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. [unreadable] [unreadable] [unreadable]