PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations.
Phosphatidylinositol 3-kinase (PI3K) promotes cell survival and communication by activating its downstream effector Akt kinase. Here we show that PS1, a protein involved in familial Alzheimer's disease (FAD), promotes cell survival by activating the PI3K/Akt cell survival signaling. This function of PS1 is unaffected by gamma-secretase inhibitors. Pharmacological and genetic evidence indicates that PS1 acts upstream of Akt, at or before PI3K kinase. PS1 forms complexes with the p85 subunit of PI3K and promotes cadherin/PI3K association. Furthermore, conditions that inhibit this association prevent the PS1-induced PI3K/Akt activation, indicating that PS1 stimulates PI3K/Akt signaling by promoting cadherin/PI3K association. By activating PI3K/Akt signaling, PS1 promotes phosphorylation/inactivation of glycogen synthase kinase-3 (GSK-3), suppresses GSK-3-dependent phosphorylation of tau at residues overphosphorylated in AD and prevents apoptosis of confluent cells. PS1 FAD mutations inhibit the PS1-dependent PI3K/Akt activation, thus promoting GSK-3 activity and tau overphosphorylation at AD-related residues. Our data raise the possibility that PS1 may prevent development of AD pathology by activating the PI3K/Akt signaling pathway. In contrast, FAD mutations may promote AD pathology by inhibiting this pathway.
Baki
Lia
L
Department of Psychiatry and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Shioi
Junichi
J
Wen
Paul
P
Shao
Zhiping
Z
Schwarzman
Alexander
A
Gama-Sosa
Miguel
M
Neve
Rachael
R
Robakis
Nikolaos K
NK
D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D002461:Cell Line, Transformed; D002470:Cell Survival; D002472:Cell Transformation, Viral; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice / Q000196:embryology; D018345:Mice, Knockout; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D053764:Presenilin-1; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018139:Simplexvirus / Q000235:genetics; D016875:tau Proteins / Q000037:antagonists & inhibitors*
D015820:Cadherins; D002219:Carbamates; D004151:Dipeptides; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D053764:Presenilin-1; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016875:tau Proteins; C410009:L 685458; C508853:PSEN1 protein, human; C494918:AKT1 protein, human