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The Journal of Neuroscience, January 9, 2008, 28(2):483-490; doi:10.1523/JNEUROSCI.4067-07.2008

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

Lia Baki,¹ Rachael L. Neve,² Zhiping Shao,¹ Junichi Shioi,¹ Anastasios Georgakopoulos,¹ and Nikolaos K Robakis¹

¹Department of Psychiatry and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York, New York 10029, and ²Department of Psychiatry and Genetics, McLean Hospital, Harvard University, Belmont, Massachusetts 02478-9106

Correspondence should be addressed to either Lia Baki or Nikolaos K. Robakis, Department of Psychiatry, Mount Sinai School of Medicine, New York University, 1 Gustave Levy Place, Box 1229, New York, NY 10029. Email: lia.baki{at}mssm.edu or Email: nikos.robakis{at}mssm.edu

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 -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.

Key words: Alzheimer's disease; apoptosis; neuronal death; Akt; phosphorylation; signaling

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Received Sept. 5, 2007; revised Oct. 21, 2007; accepted Nov. 30, 2007.

Correspondence should be addressed to either Lia Baki or Nikolaos K. Robakis, Department of Psychiatry, Mount Sinai School of Medicine, New York University, 1 Gustave Levy Place, Box 1229, New York, NY 10029. Email: lia.baki{at}mssm.edu or Email: nikos.robakis{at}mssm.edu

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