Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenoviridae / genetics
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Alzheimer Disease / genetics
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Animals
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Apoptosis*
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Carrier Proteins / metabolism
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Cells, Cultured
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Cytoskeletal Proteins / metabolism
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Down-Regulation*
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Enzyme Activation / drug effects
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Glycogen Synthase Kinase 3
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Glycogen Synthase Kinases
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Hippocampus / cytology
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JNK Mitogen-Activated Protein Kinases
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Membrane Proteins / physiology*
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Mitogen-Activated Protein Kinases*
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Mutation*
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Nerve Growth Factors / pharmacology
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Neurons / cytology*
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Neurons / drug effects
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Neurons / enzymology
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Neurons / metabolism
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PC12 Cells
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Presenilin-1
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-akt
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Rats
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Receptor, trkA*
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Ribosomal Protein S6 Kinases / metabolism
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Signal Transduction / drug effects
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Trans-Activators*
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Transfection
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Wnt Proteins
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Zebrafish Proteins*
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beta Catenin
Substances
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Carrier Proteins
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Ctnnb1 protein, rat
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Cytoskeletal Proteins
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Membrane Proteins
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Nerve Growth Factors
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Phosphoinositide-3 Kinase Inhibitors
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Presenilin-1
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Proto-Oncogene Proteins
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Trans-Activators
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Wnt Proteins
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Zebrafish Proteins
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beta Catenin
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Receptor, trkA
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Glycogen Synthase Kinases
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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Glycogen Synthase Kinase 3