PT - JOURNAL ARTICLE AU - Baki, Lia AU - Neve, Rachael L. AU - Shao, Zhiping AU - Shioi, Junichi AU - Georgakopoulos, Anastasios AU - Robakis, Nikolaos K TI - Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling AID - 10.1523/JNEUROSCI.4067-07.2008 DP - 2008 Jan 09 TA - The Journal of Neuroscience PG - 483--490 VI - 28 IP - 2 4099 - http://www.jneurosci.org/content/28/2/483.short 4100 - http://www.jneurosci.org/content/28/2/483.full SO - J. Neurosci.2008 Jan 09; 28 AB - 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 γ-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.