Mutant presenilin-1 induces apoptosis and downregulates Akt/PKB.
Most early onset cases of familial Alzheimer's disease (AD) are caused by mutations in presenilin-1 (PS1) and presenilin-2 (PS2). These mutations lead to increased beta-amyloid formation and may induce apoptosis in some model systems. Using primary cultured hippocampal neurons (HNs) and rat pheochromocytoma (PC12) cells transiently transfected with replication-defective recombinant adenoviral vectors expressing wild-type or mutant PS1, we demonstrate that mutant PS1s induce apoptosis, downregulate the survival factor Akt/PKB, and affect several Akt/PKB downstream targets, including glycogen synthase kinase-3beta and beta-catenin. Expression of a constitutively active Akt/PKB rescues HNs from mutant PS1-induced neuronal cell death, suggesting a potential therapeutic target for AD. Downregulation of Akt/PKB may be a mechanism by which mutant PS1 induces apoptosis and may play a role in the pathogenesis of familial AD.
Weihl
C C
CC
Committee on Neurobiology, University of Chicago, Chicago, Illinois 60637, USA.
Ghadge
G D
GD
Kennedy
S G
SG
Hay
N
N
Miller
R J
RJ
Roos
R P
RP
D000256:Adenoviridae / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006624:Hippocampus / Q000166:cytology; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D053764:Presenilin-1; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D020917:Receptor, trkA; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators; D014162:Transfection; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D009414:Nerve Growth Factors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D053764:Presenilin-1; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020917:Receptor, trkA; D019893:Ribosomal Protein S6 Kinases; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C495268:Ctnnb1 protein, rat; C494920:Akt1 protein, rat