Wild-type but not FAD mutant presenilin-1 prevents neuronal degeneration by promoting phosphatidylinositol 3-kinase neuroprotective signaling.
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.
Baki
Lia
L
Department of Psychiatry and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York, New York 10029, USA. lia.baki@mssm.edu
Neve
Rachael L
RL
Shao
Zhiping
Z
Shioi
Junichi
J
Georgakopoulos
Anastasios
A
Robakis
Nikolaos K
NK
D000544:Alzheimer Disease / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000166:cytology; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation / Q000502:physiology*; D009410:Nerve Degeneration / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D053764:Presenilin-1 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018139:Simplexvirus / Q000502:physiology
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D053764:Presenilin-1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D020169:Caspases