GSK-3 is essential in the pathogenesis of Alzheimer's disease.

Glycogen synthase kinase-3 (GSK-3) is a pivotal molecule in the development of Alzheimer's disease (AD). GSK-3beta is involved in the formation of paired helical filament (PHF)-tau, which is an integral component of the neurofibrillary tangle (NFT) deposits that disrupt neuronal function, and a marker of neurodegeneration in AD. GSK-3beta has exactly the same oligonucleotide sequence as tau-protein kinase I (TPKI), which was first purified from the microtubule fraction of bovine brain. Initially, we discovered that GSK-3beta was involved in amyloid-beta (Abeta)-induced neuronal death in rat hippocampal cultures. In the present review, we discuss our initial in vitro results and additional investigations showing that Abeta activates GSK-3beta through impairment of phosphatidylinositol-3 (PI3)/Akt signaling; that Abeta-activated GSK-3beta induces hyperphosphorylation of tau, NFT formation, neuronal death, and synaptic loss (all found in the AD brain); that GSK-3beta can induce memory deficits in vivo; and that inhibition of GSK-3alpha (an isoform of GSK-3beta) reduces Abeta production. These combined results strongly suggest that GSK-3 activation is a critical step in brain aging and the cascade of detrimental events in AD, preceding both the NFT and neuronal death pathways. Therefore, therapeutics targeted to inhibiting GSK-3 may be beneficial in the treatment of this devastating disease.

[1]  M. Vitek,et al.  Tau is essential to β-amyloid-induced neurotoxicity , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[2]  R. Nitsch,et al.  Formation of Neurofibrillary Tangles in P301L Tau Transgenic Mice Induced by Aβ42 Fibrils , 2001, Science.

[3]  Akihiko Takashima,et al.  Formation of Filamentous Tau Aggregations in Transgenic Mice Expressing V337M Human Tau , 2001, Neurobiology of Disease.

[4]  E. Mandelkow,et al.  Phosphorylation of tau protein by recombinant GSK‐3β: pronounced phosphorylation at select Ser/Thr‐Pro motifs but no phosphorylation at Ser262 in the repeat domain , 1999, FEBS letters.

[5]  Jen‐Shin Song,et al.  Protein Kinase FA/GSK‐3 Phosphorylates on Ser235‐Pro and Ser404‐Pro that Are Abnormally Phosphorylated in Alzheimer's Disease Brain , 1993, Journal of neurochemistry.

[6]  Christina A. Wilson,et al.  GSK-3α regulates production of Alzheimer's disease amyloid-β peptides , 2003, Nature.

[7]  J. Habener,et al.  Phosphorylation of the cAMP response element binding protein CREB by cAMP-dependent protein kinase A and glycogen synthase kinase-3 alters DNA-binding affinity, conformation, and increases net charge. , 1998, Biochemistry.

[8]  R. Davis,et al.  Rapid activation of heat shock factor-1 DNA binding by H2O2 and modulation by glutathione in human neuroblastoma and Alzheimer's disease cybrid cells. , 1999, Brain research. Molecular brain research.

[9]  K. Imahori,et al.  Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[10]  S. D’Mello,et al.  Lithium induces apoptosis in immature cerebellar granule cells but promotes survival of mature neurons. , 1994, Experimental cell research.

[11]  C. Goodman,et al.  Genetic Dissection of Structural and Functional Components of Synaptic Plasticity. III. CREB Is Necessary for Presynaptic Functional Plasticity , 1996, Neuron.

[12]  K. Imahori,et al.  Localization and Developmental Changes of τ Protein Kinase I/Glycogen Synthase Kinase‐3β in Rat Brain , 1994 .

[13]  M. Montminy,et al.  The CREB family of transcription activators. , 1992 .

[14]  J. Lucas,et al.  Spatial learning deficit in transgenic mice that conditionally over‐express GSK‐3β in the brain but do not form tau filaments , 2002, Journal of neurochemistry.

[15]  S. Lovestone,et al.  The phosphorylation of tau: a critical stage in neurodevelopment and neurodegenerative processes. , 1997, Neuroscience.

[16]  J. Ávila,et al.  Lithium protects cultured neurons against β‐amyloid‐induced neurodegeneration , 1999 .

[17]  G. Johnson,et al.  Tau protein in normal and Alzheimer's disease brain. , 1999, Journal of Alzheimer's disease : JAD.

[18]  E. Kandel,et al.  Activation of cAMP-Responsive genes by stimuli that produce long-term facilitation in aplysia sensory neurons , 1993, Neuron.

[19]  M. Greenberg,et al.  CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. , 1991, Science.

[20]  C. Volonté,et al.  Lithium chloride promotes short-term survival of PC12 cells after serum and NGF deprivation , 1993 .

[21]  J. Hanover,et al.  Nuclear glycogen and glycogen synthase kinase 3. , 1998, Biochemical and biophysical research communications.

[22]  M. Greenberg,et al.  Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB , 1994, Cell.

[23]  E. Mandelkow,et al.  The endogenous and cell cycle-dependent phosphorylation of tau protein in living cells: implications for Alzheimer's disease. , 1998, Molecular biology of the cell.

[24]  J L McGaugh,et al.  Antisense oligodeoxynucleotide-mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Brion,et al.  Developmental expression and localization of glycogen synthase kinase-3β in rat brain , 1999, Journal of Chemical Neuroanatomy.

[26]  K. Imahori,et al.  Tau protein kinase I is essential for amyloid beta-protein-induced neurotoxicity. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Montminy,et al.  Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene , 1987, Nature.

[28]  M. Spillantini,et al.  Tau gene mutations: dissecting the pathogenesis of FTDP-17. , 2002, Trends in molecular medicine.

[29]  Brendan D. Price,et al.  Sequential Phosphorylation by Mitogen-activated Protein Kinase and Glycogen Synthase Kinase 3 Represses Transcriptional Activation by Heat Shock Factor-1* , 1996, The Journal of Biological Chemistry.

[30]  J. Woodgett,et al.  Molecular cloning and expression of glycogen synthase kinase‐3/factor A. , 1990, The EMBO journal.

[31]  S. Lovestone,et al.  GSK-3β inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila , 2004, Molecular Psychiatry.

[32]  G. Johnson,et al.  Tau protein in normal and Alzheimer's disease brain: an update. , 1999, Journal of Alzheimer's disease : JAD.

[33]  R. Jope,et al.  The multifaceted roles of glycogen synthase kinase 3β in cellular signaling , 2001, Progress in Neurobiology.

[34]  C. Masters,et al.  Alternative transcripts of presenilin‐1 associated with frontotemporal dementia , 2002, Neuroreport.

[35]  K. Imahori,et al.  Tau protein kinase I converts normal tau protein into A68-like component of paired helical filaments. , 1992, The Journal of biological chemistry.

[36]  J. Woodgett,et al.  Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: Generation of paired helical filament epitopes and neuronal localisation of the kinase , 1992, Neuroscience Letters.

[37]  M. Hutton Molecular genetics of chromosome 17 tauopathies , 2000, Neurobiology of Aging.

[38]  M. Goedert,et al.  Tau mutations in frontotemporal dementia FTDP-17 and their relevance for Alzheimer's disease. , 2000, Biochimica et biophysica acta.

[39]  D. Selkoe,et al.  The Role of APP Processing and Trafficking Pathways in the Formation of Amyloid β‐Protein a , 1996 .

[40]  K. Imahori,et al.  Characterization of tau phosphorylation in glycogen synthase kinase-3beta and cyclin dependent kinase-5 activator (p23) transfected cells. , 1998, Biochimica et biophysica acta.

[41]  T. Hashikawa,et al.  Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Mark P Mattson,et al.  Alzheimer's Presenilin 1 Mutations Impair Kinesin-Based Axonal Transport , 2003, The Journal of Neuroscience.

[43]  C. van Broeckhoven,et al.  A novel presenilin 1 mutation associated with Pick's disease but not β‐amyloid plaques , 2004, Annals of neurology.

[44]  W. Blackstock,et al.  Phosphorylation Sites on Tau Identified by Nanoelectrospray Mass Spectrometry , 2000, Journal of neurochemistry.

[45]  K. Imahori,et al.  Amyloid β peptide induces cytoplasmic accumulation of amyloid protein precursor via tau protein kinase I/glycogen synthase kinase-3β in rat hippocampal neurons , 1995, Neuroscience Letters.

[46]  H. Braak,et al.  Diagnostic Criteria for Neuropathologic Assessment of Alzheimer’s Disease , 1997, Neurobiology of Aging.

[47]  M. Mercken,et al.  Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[48]  P. Cohen,et al.  A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. , 2001, Molecular Cell.

[49]  G. Drewes,et al.  Glycogen synthase kinase‐3 and the Alzheimer‐like state of microtubule‐associated protein tau , 1992, FEBS letters.

[50]  K. Heidenreich,et al.  Insulin-like Growth Factor-I Induces bcl-2 Promoter through the Transcription Factor cAMP-Response Element-binding Protein* , 1999, The Journal of Biological Chemistry.

[51]  K. Deisseroth,et al.  Signaling from Synapse to Nucleus: Postsynaptic CREB Phosphorylation during Multiple Forms of Hippocampal Synaptic Plasticity , 1996, Neuron.

[52]  Michael E. Greenberg,et al.  Coupling of the RAS-MAPK Pathway to Gene Activation by RSK2, a Growth Factor-Regulated CREB Kinase , 1996, Science.

[53]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[54]  J. Kiang,et al.  Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology. , 1998, Pharmacology & therapeutics.

[55]  Richard Hollister,et al.  Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease , 1997, Annals of neurology.

[56]  D. Chuang,et al.  Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[57]  K. Imahori,et al.  Glycogen synthase kinase 3β is identical to tau protein kinase I generating several epitopes of paired helical filaments , 1993 .

[58]  D. Selkoe,et al.  Toward a Comprehensive Theory for Alzheimer's Disease. Hypothesis: Alzheimer's Disease Is Caused by the Cerebral Accumulation and Cytotoxicity of Amyloid β‐Protein , 2000, Annals of the New York Academy of Sciences.

[59]  R. Morimoto,et al.  Repression of the heat shock factor 1 transcriptional activation domain is modulated by constitutive phosphorylation , 1997, Molecular and cellular biology.

[60]  Nancy Ratner,et al.  Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin‐based motility , 2002, The EMBO journal.

[61]  R. Petersen,et al.  Familial Frontotemporal Dementia Associated with a Novel Presenilin-1 Mutation , 2002, Dementia and Geriatric Cognitive Disorders.

[62]  T. Hashikawa,et al.  Aberrant Tau Phosphorylation by Glycogen Synthase Kinase-3β and JNK3 Induces Oligomeric Tau Fibrils in COS-7 Cells* , 2002, The Journal of Biological Chemistry.

[63]  R. Morimoto,et al.  Regulation of the Heat Shock Transcriptional Response: Cross Talk between a Family of Heat Shock Factors, Molecular Chaperones, and Negative Regulators the Heat Shock Factor Family: Redundancy and Specialization , 2022 .

[64]  L. Boxer,et al.  CREB Proteins Function as Positive Regulators of the Translocated bcl-2 Allele in t(14;18) Lymphomas* , 1996, The Journal of Biological Chemistry.

[65]  M. Roussel,et al.  Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. , 1998, Genes & development.

[66]  K. Imahori,et al.  Analysis of phosphorylation of tau with antibodies specific for phosphorylation sites , 1995, Neuroscience Letters.

[67]  Alcino J. Silva,et al.  CREB and memory. , 1998, Annual review of neuroscience.

[68]  L. Boxer,et al.  Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis , 1996, Molecular and cellular biology.

[69]  L. Partridge,et al.  Insulin/IGF signalling and ageing: seeing the bigger picture. , 2001, Current opinion in genetics & development.

[70]  W. Kamphorst,et al.  Phenotypic Variation in Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 , 2004, Dementia and Geriatric Cognitive Disorders.

[71]  K. Imahori,et al.  Exposure of rat hippocampal neurons to amyloid β peptide (25–35) induces the inactivation of phosphatidyl inositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3β , 1996, Neuroscience Letters.

[72]  P. Roach,et al.  A secondary phosphorylation of CREB341 at Ser129 is required for the cAMP-mediated control of gene expression. A role for glycogen synthase kinase-3 in the control of gene expression. , 1994, The Journal of biological chemistry.

[73]  W. Schmid,et al.  Targeting of the CREB gene leads to up‐regulation of a novel CREB mRNA isoform. , 1996, The EMBO journal.

[74]  C. M. Davenport,et al.  Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. , 1999, Science.

[75]  R. Jope,et al.  Glycogen Synthase Kinase-3β Facilitates Staurosporine- and Heat Shock-induced Apoptosis , 2000, The Journal of Biological Chemistry.

[76]  N. Mivechi,et al.  Glycogen Synthase Kinase 3β and Extracellular Signal-Regulated Kinase Inactivate Heat Shock Transcription Factor 1 by Facilitating the Disappearance of Transcriptionally Active Granules after Heat Shock , 1998, Molecular and Cellular Biology.

[77]  K. Imahori,et al.  Physiology and pathology of tau protein kinases in relation to Alzheimer's disease. , 1997, Journal of biochemistry.

[78]  M. Billingsley,et al.  Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration. , 1997, The Biochemical journal.

[79]  A. Harwood,et al.  Regulation of GSK-3 A Cellular Multiprocessor , 2001, Cell.

[80]  P. Shaw,et al.  Molecular Cloning and Characterization of the Human Glycogen Synthase Kinase-3β Promoter , 1999 .

[81]  K. Imahori,et al.  A novel tubulin-dependent protein kinase forming a paired helical filament epitope on tau. , 1988, Journal of biochemistry.

[82]  S. Lovestone,et al.  Phosphorylation of tau by glycogen synthase kinase-3β in intact mammalian cells: The effects on the organization and stability of microtubules , 1996, Neuroscience.

[83]  M. Goedert,et al.  Tau protein pathology in neurodegenerative diseases , 1998, Trends in Neurosciences.

[84]  K. Ishiguro,et al.  Distribution of tau protein kinase I/glycogen synthase kinase-3β, phosphatases 2A and 2B, and phosphorylated tau in the developing rat brain , 2000, Brain Research.

[85]  Martin Holzenberger,et al.  IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice , 2003, Nature.

[86]  M. Hagiwara,et al.  Recombinant cyclic AMP response element binding protein (CREB) phosphorylated on Ser-133 is transcriptionally active upon its introduction into fibroblast nuclei. , 1994, The Journal of biological chemistry.

[87]  Ssang-Goo Cho,et al.  Glycogen Synthase Kinase 3β Is a Natural Activator of Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase Kinase 1 (MEKK1)* , 2003, The Journal of Biological Chemistry.