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

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

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

Lia Baki,Rachael L Neve,Zhiping Shao,Junichi Shioi,Anastasios Georgakopoulos,Nikolaos K Robakis,Lia Baki,Rachael L Neve,Zhiping Shao,Junichi Shioi,Anastasios Georgakopoulos,Nikolaos K Robakis,Lia Baki,Rachael L Neve,Zhiping Shao,Junichi Shioi,Anastasios Georgakopoulos,Nikolaos K Robakis,

The role of presenilin-1 (PS1) in neuronal phosphatidylinositol 3-kinase (PI3K)/Akt signaling was investigated in primary neuronal cultures from wild-type (WT) and PS1 null (PS1-/-) embryonic mouse brains. Here we show that in PS1-/- cultures, the onset of neuronal maturation coincides with a decrease in the PI3K-dependent phosphorylation-activation of Akt and phosphorylation-inactivation of glycogen synthase kinase-3 (GSK-3). Mature PS1-/- neurons show increased activation of apoptotic caspase-3 and progressive degeneration preceded by dendritic retraction. Expression of exogenous WT PS1 or constitutively active Akt in PS1-/- neurons stimulates PI3K signaling and suppresses both caspase-3 activity and dendrite retraction. The survival effects of PS1 are sensitive to inhibitors of PI3K kinase but insensitive to gamma-secretase inhibitors. Familial Alzheimer disease (FAD) mutations suppress the ability of PS1 to promote PI3K/AKT signaling, prevent phosphorylation/inactivation of GSK-3 and promote activation of caspase-3. These mutation effects are reversed upon coexpression of constitutively active Akt. Together, our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients.

Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling. Publishing Authors By Initials

L Baki,RL Neve,Z Shao,J Shioi,A Georgakopoulos,NK Robakis,L Baki,RL Neve,Z Shao,J Shioi,A Georgakopoulos,NK Robakis,L Baki,RL Neve,Z Shao,J Shioi,A Georgakopoulos,NK Robakis,

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

PUBLICATION TYPE: Journal Article

Journal: The Journal of neuroscience : the official journal

VOLUME: 28

Page Numbers: 483-90

Journal Abbreviation: J. Neurosci.

ISSN: 1529-2401

DAY: 9

MONTH: Jan

YEAR: 2008

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

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LANGUAGE: eng

NlmUniqueID: 8102140

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AFFILIATION: Department of Psychiatry and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York, New York 10029, and Department of Psychiatry and Genetics, McLean Hospital, Harvard University, Belmont, Massachusetts 02478-9106.

Country: United States

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MEDLINETA: J Neurosci

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