Increased cell death is a hallmark of neurodegenerative diseases including Alzheimer's disease (AD). The PI3K/Akt signaling pathway plays critical roles in cell survival. Its targets include components of the cell death machinery, like the BCL-2 and FOXO families, transcription factors important for cell survival, and kinases like GSK3_ involved in the generation of neurofibrillary tangles (NFT) of Alzheimer's disease. Presenilin 1 (PS1) is a transmembrane protein involved in familial Alzheimer's disease (FAD). Classic cadherins, including epithelial (E)- and neural (N)-cadherins, are major cell-cell adhesion receptors involved in the development, maintenance and function of almost all solid tissues. PS1 binds cadherins and regulates their function and processing. Using PSI+/+ and PS1 knockout (PS1-/-) fibroblasts we noticed that absence of PS1 correlates with apoptotic cell death and decreased activity of the PI3K/Akt cell survival pathway. Re-introduction of PS1 in PSI-/- cells activates the PI3K/Akt pathway and rescues cells from apoptosis suggesting that PS1 mediates transmission of survival signals. PSI-induced cell survival requires PI3K activity. These data indicate that PS1 activates the PI3K/Akt pathway. Cadherin adhesion stimulates the PI3K/Akt pathway by promoting cadherin association with the p85 subunit of PI3K. Our data show that PS1 stabilizes the cadherin/p85 association suggesting a mechanism for the PS1 cell survival effects. Furthermore, we obtained evidence that PS1 is important for insulin growth factor (IGF)-induced stimulation of the PI3K/Akt pathway, suggesting that PS1 may be involved in tyrosine kinase receptor signaling. Several PS1 FAD mutants showed a decreased ability to activate Akt or to phosphorylate GSK3[3 kinase. Here we propose to investigate the cell survival function of PS1, the mechanisms involved in the PSI-mediated activation of the PI3K/Akt pathway and the effects of PS1 FAD mutations on the activation of the PI3K/Akt pathway and on cell survival. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047229-04
Application #
7173255
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Refolo, Lorenzo
Project Start
2004-01-01
Project End
2008-12-31
Budget Start
2007-01-01
Budget End
2008-12-31
Support Year
4
Fiscal Year
2007
Total Cost
$371,658
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
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