The Role of Mitogen-Activated Protein Kinase Pathways in Alzheimer’s Disease

Given the critical role of mitogen-activated protein kinase (MAPK) pathways in regulating cellular processes that are affected in Alzheimer’s disease (AD), the importance of MAPKs in disease pathogenesis is being increasingly recognized. All MAPK pathways, i.e., the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 pathways, are activated in vulnerable neurons in patients with AD suggesting that MAPK pathways are involved in the pathophysiology and pathogenesis of AD. Here we review recent findings implicating the MAPK pathways in AD and discuss the relationship between these pathways and the prominent pathological processes, i.e., tau phosphorylation and amyloid-β deposition, as well as the functional association to amyloid β protein precursor. We suggest that regulation of these pathways may be a central facet to any potential treatment for the disease.

[1]  E. Matsubara,et al.  Abeta amyloidosis induces the initial stage of tau accumulation in APP(Sw) mice. , 2001, Neuroscience letters.

[2]  J. Hendricks,et al.  The role of the MAP-kinase superfamily in beta-amyloid toxicity. , 2001, Metabolic brain disease.

[3]  P. Lograsso,et al.  Signalling for survival and death in neurones: the role of stress-activated kinases, JNK and p38. , 2001, Cellular signalling.

[4]  K. Titani,et al.  Hyperphosphorylation of Tau in PHF , 1995, Neurobiology of Aging.

[5]  K. Malik,et al.  Activation of the L voltage-sensitive calcium channel by mitogen-activated protein (MAP) kinase following exposure of neuronal cells to beta-amyloid. MAP kinase mediates beta-amyloid-induced neurodegeneration. , 1999, The Journal of biological chemistry.

[6]  T. Murphy,et al.  Activation of p42 Mitogen‐Activated Protein Kinase by Glutamate Receptor Stimulation in Rat Primary Cortical Cultures , 1993, Journal of neurochemistry.

[7]  M. Rapoport,et al.  PD98059 Prevents Neurite Degeneration Induced by Fibrillar β‐Amyloid in Mature Hippocampal Neurons , 2000, Journal of neurochemistry.

[8]  Virginia M. Y. Lee,et al.  Staging of neurofibrillary degeneration caused by human tau overexpression in a unique cellular model of human tauopathy. , 2001, The American journal of pathology.

[9]  K. Guan,et al.  Signaling molecules involved in coupling growth hormone receptor to mitogen-activated protein kinase activation. , 1997, Endocrinology.

[10]  Jiahuai Han,et al.  Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms , 1995, Science.

[11]  S. Papasozomenos,et al.  tau kinases in the rat heat shock model: possible implications for Alzheimer disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[12]  H. Nawashiro,et al.  Differential Activation of Mitogen-Activated Protein Kinase Pathways after Traumatic Brain Injury in the Rat Hippocampus , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[13]  R. Huganir,et al.  SynGAP: a Synaptic RasGAP that Associates with the PSD-95/SAP90 Protein Family , 1998, Neuron.

[14]  S. Lovestone,et al.  Stimulation of MAP kinase by v‐raf transformation of fibroblasts fails to induce hyperphosphorylation of transfected tau , 1995, FEBS letters.

[15]  G. Perry,et al.  Metabolic, metallic, and mitotic sources of oxidative stress in Alzheimer disease. , 2000, Antioxidants & redox signaling.

[16]  C. Cotman,et al.  Differential Induction of Immediate Early Gene Proteins in Cultured Neurons by β‐Amyloid (Aβ): Association of c‐Jun with Aβ‐Induced Apoptosis , 1995 .

[17]  P. Dash,et al.  A Mitogen-Activated Protein Kinase Cascade in the CA1/CA2 Subfield of the Dorsal Hippocampus Is Essential for Long-Term Spatial Memory , 1999, The Journal of Neuroscience.

[18]  Xiongwei Zhu,et al.  Cell cycle events in neurons. Proliferation or death? , 1999, The American journal of pathology.

[19]  G. Drewes,et al.  Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer‐like state. , 1992, The EMBO journal.

[20]  Wei Guo,et al.  Characterization of the Structure and Function of a New Mitogen-activated Protein Kinase (p38β)* , 1996, The Journal of Biological Chemistry.

[21]  T. Shea,et al.  Hyperactivation of Mitogen-Activated Protein Kinase Increases Phospho-Tau Immunoreactivity Within Human Neuroblastoma: Additive and Synergistic Influence of Alteration of Additional Kinase Activities , 1999, Cellular and Molecular Neurobiology.

[22]  R. Heumann,et al.  Activation of mitogen-activated protein kinase cascade and phosphorylation of cytoskeletal proteins after neurone-specific activation of p21ras. II. Cytoskeletal proteins and dendritic morphology , 2001, Neuroscience.

[23]  H. Itoh,et al.  Amyloid beta protein precursor is involved in the growth of human colon carcinoma cell in vitro and in vivo. , 2001, International journal of cancer.

[24]  Simon Lovestone,et al.  Alzheimer's disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells , 1994, Current Biology.

[25]  M. Billingsley,et al.  Tau phosphorylation in brain slices: pharmacological evidence for convergent effects of protein phosphatases on tau and mitogen-activated protein kinase. , 1995, Molecular pharmacology.

[26]  John A. Martin,et al.  Localization of the mitogen activated protein kinase ERK2 in Alzheimer's disease neurofibrillary tangles and senile plaque neurites , 1993, Brain Research.

[27]  Y. Dudai,et al.  Specific and Differential Activation of Mitogen-Activated Protein Kinase Cascades by Unfamiliar Taste in the Insular Cortex of the Behaving Rat , 1998, The Journal of Neuroscience.

[28]  Jae-Chang Jung,et al.  Mitogen-Activated Protein Kinase Inhibition in Traumatic Brain Injury: In Vitro and In Vivo Effects , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[29]  D. Flood,et al.  Activation of c-Jun N-Terminal Kinase and p38 in an Alzheimer's Disease Model Is Associated with Amyloid Deposition , 2002, The Journal of Neuroscience.

[30]  T. Bliss,et al.  The Role of Extracellular Regulated Kinases I/II in Late-Phase Long-Term Potentiation , 2002, The Journal of Neuroscience.

[31]  Scott T. Wong,et al.  Cross Talk between ERK and PKA Is Required for Ca2+ Stimulation of CREB-Dependent Transcription and ERK Nuclear Translocation , 1998, Neuron.

[32]  S. Gammeltoft,et al.  Role and regulation of 90 kDa ribosomal S6 kinase (RSK) in signal transduction , 1999, Molecular and Cellular Endocrinology.

[33]  D. Bozyczko‐Coyne,et al.  CEP‐1347/KT‐7515, an inhibitor of SAPK/JNK pathway activation, promotes survival and blocks multiple events associated with Aβ‐induced cortical neuron apoptosis , 2001, Journal of neurochemistry.

[34]  I. Kanazawa,et al.  JNK activation is associated with intracellular beta-amyloid accumulation. , 2000, Brain research. Molecular brain research.

[35]  Anirvan Ghosh,et al.  Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF , 1995, Nature.

[36]  A. Reith,et al.  Differential activation of MAPK/ERK and p38/SAPK in neurones and glia following focal cerebral ischaemia in the rat. , 2000, Brain research. Molecular brain research.

[37]  K. Lau,et al.  Phosphorylation of thr668 in the cytoplasmic domain of the Alzheimer's disease amyloid precursor protein by stress‐activated protein kinase 1b (Jun N‐terminal kinase‐3) , 2001 .

[38]  Jeffrey A. Johnson,et al.  Lack of Neurodegeneration in Transgenic Mice Overexpressing Mutant Amyloid Precursor Protein Is Associated with Increased Levels of Transthyretin and the Activation of Cell Survival Pathways , 2002, The Journal of Neuroscience.

[39]  Xiantao Wang,et al.  Signaling Events in Amyloid β-Peptide-induced Neuronal Death and Insulin-like Growth Factor I Protection* , 2002, The Journal of Biological Chemistry.

[40]  S. Estus,et al.  Aggregated Amyloid-β Protein Induces Cortical Neuronal Apoptosis and Concomitant “Apoptotic” Pattern of Gene Induction , 1997, The Journal of Neuroscience.

[41]  M. Szyf,et al.  Phosphorylation of mitogen-activated protein kinase is altered in neuroectodermal cells overexpressing the human amyloid precursor protein 751 isoform. , 1999, Brain research. Molecular brain research.

[42]  C. Chu,et al.  Sustained extracellular signal‐regulated kinase activation by 6‐hydroxydopamine: implications for Parkinson's disease , 2001, Journal of neurochemistry.

[43]  W. Markesbery,et al.  p38 Kinase Is Activated in the Alzheimer's Disease Brain , 1999, Journal of neurochemistry.

[44]  M. Youdim,et al.  Non-steroidal Anti-inflammatory Drugs Stimulate Secretion of Non-amyloidogenic Precursor Protein* , 2002, The Journal of Biological Chemistry.

[45]  S. Fujita,et al.  Inhibition of Protein Phosphatase 2A Overrides Tau Protein Kinase I/Glycogen Synthase Kinase 3β and Cyclin-dependent Kinase 5 Inhibition and Results in Tau Hyperphosphorylation in the Hippocampus of Starved Mouse* , 2001, The Journal of Biological Chemistry.

[46]  Alejandra del C. Alonso,et al.  Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules , 1996, Nature Medicine.

[47]  Michael E. Greenberg,et al.  Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis , 1995, Science.

[48]  A. Nebreda,et al.  Reactivating kinase/p38 phosphorylates tau protein in vitro. , 1997, Journal of neurochemistry.

[49]  D. Braguer,et al.  Hyperphosphorylation of tau is mediated by ERK activation during anticancer drug‐induced apoptosis in neuroblastoma cells , 2001, Journal of neuroscience research.

[50]  M. Karin,et al.  Mammalian MAP kinase signalling cascades , 2001, Nature.

[51]  Y. Christen,et al.  Identification of β-Amyloid-Responsive Genes by RNA Differential Display: Early Induction of a DNA Damage-Inducible Gene, gadd45 , 1999, Experimental Neurology.

[52]  J. David Sweatt,et al.  β-Amyloid Activates the Mitogen-Activated Protein Kinase Cascade via Hippocampal α7 Nicotinic Acetylcholine Receptors:In Vitro and In Vivo Mechanisms Related to Alzheimer's Disease , 2001, The Journal of Neuroscience.

[53]  J. Girault,et al.  The ERK/MAP-kinases cascade in the nervous system. , 1999, Neuroreport.

[54]  E. Yavin,et al.  ERK activation and nuclear translocation in amyloid‐β peptide‐ and iron‐stressed neuronal cell cultures , 2002, The European journal of neuroscience.

[55]  A. Coogan,et al.  The p38 mitogen-activated protein kinase inhibitor SB203580 antagonizes the inhibitory effects of interleukin-1β on long-term potentiation in the rat dentate gyrus in vitro , 1999, Neuroscience.

[56]  T. Ogihara,et al.  Elevated amyloid β protein(1-40) level induces CREB phosphorylation at serine-133 via p44/42 MAP kinase (Erk1/2)-dependent pathway in rat pheochromocytoma PC12 cells , 1997 .

[57]  R. Roncarati,et al.  Jun NH2-terminal Kinase (JNK) Interacting Protein 1 (JIP1) Binds the Cytoplasmic Domain of the Alzheimer's β-Amyloid Precursor Protein (APP)* , 2002, The Journal of Biological Chemistry.

[58]  Y. Kirino,et al.  Differential Roles of JIP Scaffold Proteins in the Modulation of Amyloid Precursor Protein Metabolism* , 2002, The Journal of Biological Chemistry.

[59]  J. Sweatt,et al.  Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer's disease. , 2001, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[60]  D. Selkoe,et al.  Alzheimer's Disease--Genotypes, Phenotype, and Treatments , 1997, Science.

[61]  G. Perry,et al.  Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[62]  P. Crespo,et al.  The small GTP-binding proteins Rac1 and Cdc42regulate the activity of the JNK/SAPK signaling pathway , 1995, Cell.

[63]  V. Ingram,et al.  Brain protein kinase PK40erk converts TAU into a PHF-like form as found in Alzheimer's disease. , 1993, Biochemical and biophysical research communications.

[64]  I. Ferrer,et al.  Phosphorylated Map Kinase (ERK1, ERK2) Expression is Associated with Early Tau Deposition in Neurones and Glial Cells, but not with Increased Nuclear DNA Vulnerability and Cell Death, in Alzheimer Disease, Pick's Disease, Progressive Supranuclear Palsy and Corticobasal Degeneration , 2001, Brain pathology.

[65]  S Shimohama,et al.  Activation of MKK6, an upstream activator of p38, in Alzheimer's disease , 2001, Journal of neurochemistry.

[66]  W. Blackstock,et al.  New Phosphorylation Sites Identified in Hyperphosphorylated Tau (Paired Helical Filament‐Tau) from Alzheimer's Disease Brain Using Nanoelectrospray Mass Spectrometry , 1998, Journal of neurochemistry.

[67]  J. David Sweatt,et al.  A Requirement for the Mitogen-activated Protein Kinase Cascade in Hippocampal Long Term Potentiation* , 1997, The Journal of Biological Chemistry.

[68]  V. Ingram,et al.  Hyperphosphorylation of human TAU by brain kinase PK40erk beyond phosphorylation by cAMP-dependent PKA: relation to Alzheimer's disease. , 1994, Biochemical and biophysical research communications.

[69]  H. Kawasaki,et al.  Requirement for Mitogen-activated Protein Kinase in Cerebellar Long Term Depression* , 1999, The Journal of Biological Chemistry.

[70]  C. Behl,et al.  Testosterone stimulates rapid secretory amyloid precursor protein release from rat hypothalamic cells via the activation of the mitogen-activated protein kinase pathway , 2000, Neuroscience Letters.

[71]  M. Vergnes,et al.  Repetitive electroconvulsive seizures induce activity of c-Jun N-terminal kinase and compartment-specific desensitization of c-Jun phosphorylation in the rat brain. , 1999, Brain research. Molecular brain research.

[72]  T. Hiraki,et al.  c-Jun N-Terminal Kinase (JNK)-Interacting Protein-1b/Islet-Brain-1 Scaffolds Alzheimer's Amyloid Precursor Protein with JNK , 2001, The Journal of Neuroscience.

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

[74]  T. Ogihara,et al.  Elevated amyloid beta protein(1-40) level induces CREB phosphorylation at serine-133 via p44/42 MAP kinase (Erk1/2)-dependent pathway in rat pheochromocytoma PC12 cells. , 1997, Biochemical and Biophysical Research Communications - BBRC.

[75]  N. Holbrook,et al.  Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation. , 1999, Neuroreport.

[76]  N. Sato,et al.  Activated cAMP-response Element-binding Protein Regulates Neuronal Expression of Presenilin-1* , 2001, The Journal of Biological Chemistry.

[77]  Yong Jiang,et al.  Characterization of the Structure and Function of the Fourth Member of p38 Group Mitogen-activated Protein Kinases, p38δ* , 1997, The Journal of Biological Chemistry.

[78]  Philip R. Cohen,et al.  Phosphorylation of microtubule‐associated protein tau by stress‐activated protein kinases , 1997, FEBS letters.

[79]  S. Grewal,et al.  Extracellular-signal-regulated kinase signalling in neurons , 1999, Current Opinion in Neurobiology.

[80]  K. Mielke,et al.  JNK and p38 stresskinases — degenerative effectors of signal-transduction-cascades in the nervous system , 2000, Progress in Neurobiology.

[81]  D. Selkoe,et al.  Secreted beta-amyloid precursor protein stimulates mitogen-activated protein kinase and enhances tau phosphorylation. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[82]  J. Wood,et al.  Functional studies of Alzheimer's disease tau protein , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[83]  N. Neff,et al.  Chronic sparing of delayed alternation performance and choline acetyltransferase activity by CEP-1347/KT-7515 in rats with lesions of nucleus basalis magnocellularis , 1998, Neuroscience.

[84]  B. Hyman,et al.  Demonstration by fluorescence resonance energy transfer of a close association between activated MAP kinase and neurofibrillary tangles: implications for MAP kinase activation in Alzheimer disease. , 1999, Journal of neuropathology and experimental neurology.

[85]  D. Selkoe Alzheimer's disease: genotypes, phenotypes, and treatments. , 1997, Science.

[86]  S. Younkin,et al.  Regulation of Amyloid Precursor Protein Processing by Presenilin 1 (PS1) and PS2 in PS1 Knockout Cells* , 2000, The Journal of Biological Chemistry.

[87]  H. Wiśniewski,et al.  Neurofibrillary tangles of paired helical filaments , 1976, Journal of the Neurological Sciences.

[88]  Y. Kirino,et al.  Interaction of Alzheimer's β-Amyloid Precursor Family Proteins with Scaffold Proteins of the JNK Signaling Cascade* , 2002, The Journal of Biological Chemistry.

[89]  P. Rakic,et al.  Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene , 1997, Nature.

[90]  A. Nebreda,et al.  Reactivating Kinase/p38 Phosphorylates τ Protein In Vitro , 1997 .

[91]  W. Daniels,et al.  The Role of the MAP-Kinase Superfamily in β-Amyloid Toxicity , 2001, Metabolic Brain Disease.

[92]  Xiongwei Zhu,et al.  Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the ‘two hit’ hypothesis , 2001, Mechanisms of Ageing and Development.

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

[94]  R. Flavell,et al.  Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[95]  George Perry,et al.  Activation of p38 Kinase Links Tau Phosphorylation, Oxidative Stress, and Cell Cycle‐Related Events in Alzheimer Disease , 2000 .

[96]  I. Kanazawa,et al.  JNK activation is associated with intracellular β-amyloid accumulation , 2000 .

[97]  S. Heck,et al.  Estrogen induces a rapid secretion of amyloid beta precursor protein via the mitogen-activated protein kinase pathway. , 2001, European journal of biochemistry.

[98]  A. A. Parsons,et al.  Therapeutic potential of anti-inflammatory drugs in focal stroke , 2000, Expert opinion on investigational drugs.

[99]  T. Hunter,et al.  p38-2, a Novel Mitogen-activated Protein Kinase with Distinct Properties* , 1997, The Journal of Biological Chemistry.

[100]  A. Coogan,et al.  P42/44 MAP kinase inhibitor PD98059 attenuates multiple forms of synaptic plasticity in rat dentate gyrus in vitro. , 1999, Journal of neurophysiology.

[101]  M. Greenberg,et al.  Membrane depolarization and calcium influx stimulate MEK and MAP kinase via activation of Ras , 1994, Neuron.

[102]  Ashley I. Bush,et al.  Redox-active iron mediates amyloid-β toxicity , 2001 .

[103]  M. Greenberg,et al.  β-Amyloid Induces Neuronal Apoptosis Via a Mechanism that Involves the c-Jun N-Terminal Kinase Pathway and the Induction of Fas Ligand , 2001, The Journal of Neuroscience.

[104]  U. Ueberham,et al.  Regulated secretion of amyloid precursor protein by TrkA receptor stimulation in rat pheochromocytoma-12 cells is mitogen activated protein kinase sensitive , 1999, Neuroscience Letters.

[105]  S. Lovestone,et al.  Dishevelled Regulates the Metabolism of Amyloid Precursor Protein via Protein Kinase C/Mitogen-Activated Protein Kinase and c-Jun Terminal Kinase , 2001, The Journal of Neuroscience.

[106]  P. Greengard,et al.  Regulation of Secretion of Alzheimer Amyloid Precursor Protein by the Mitogen‐Activated Protein Kinase Cascade , 1998, Journal of neurochemistry.

[107]  Jiahuai Han,et al.  The primary structure of p38 gamma: a new member of p38 group of MAP kinases. , 1996, Biochemical and biophysical research communications.

[108]  B. Hyman,et al.  Extracellular signal regulated kinases. Localization of protein and mRNA in the human hippocampal formation in Alzheimer's disease. , 1994, The American journal of pathology.

[109]  E. Matsubara,et al.  Aβ amyloidosis induces the initial stage of tau accumulation in APPSw mice , 2001, Neuroscience Letters.

[110]  M. Cobb,et al.  Mitogen-activated protein kinase pathways. , 1997, Current opinion in cell biology.

[111]  I. Nishimoto,et al.  Multiple Mechanisms Underlie Neurotoxicity by Different Types of Alzheimer's Disease Mutations of Amyloid Precursor Protein* , 2000, The Journal of Biological Chemistry.

[112]  M. Goedert,et al.  Phosphorylation of microtubule‐associated protein tau by stress‐activated protein kinases in intact cells , 2002, FEBS letters.

[113]  β‐Amyloid‐induced neuronal apoptosis requires c‐Jun N‐terminal kinase activation , 2001, Journal of neurochemistry.

[114]  J. Egan,et al.  Amyloid precursor protein requires the insulin signaling pathway for neurotrophic activity. , 1997, Brain research. Molecular brain research.

[115]  K. Abe,et al.  Amyloid β neurotoxicity not mediated by the mitogen-activated protein kinase cascade in cultured rat hippocampal and cortical neurons , 2000, Neuroscience Letters.

[116]  M. Greenberg,et al.  Ca2+-Dependent Routes to Ras: Mechanisms for Neuronal Survival, Differentiation, and Plasticity? , 1996, Neuron.

[117]  C. Cotman,et al.  DNA damage and apoptosis in Alzheimer's disease: colocalization with c- Jun immunoreactivity, relationship to brain area, and effect of postmortem delay , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[118]  B. Anderton,et al.  Stress‐Activated Protein Kinase/c‐Jun N‐Terminal Kinase Phosphorylates τ Protein , 1997, Journal of neurochemistry.

[119]  Á. Pascual,et al.  Nerve growth factor modulates the expression and secretion of β‐amyloid precursor protein through different mechanisms in PC12 cells , 2001, Journal of neurochemistry.

[120]  J. Sweatt,et al.  The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory , 2001, Journal of neurochemistry.

[121]  I. Nishimoto,et al.  Cell surface receptor function of amyloid precursor protein that activates Ser/Thr kinases. , 1996, Gerontology.

[122]  L. Mucke,et al.  Dynamic regulation of c-Jun N-terminal kinase activity in mouse brain by environmental stimuli. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[123]  Xiongwei Zhu,et al.  Activation and redistribution of c‐Jun N‐terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's disease , 2001, Journal of neurochemistry.

[124]  Mark A. Smith,et al.  Signal transduction abnormalities in Alzheimer's disease: evidence of a pathogenic stimuli , 1999, Brain Research.

[125]  K. Nozaki,et al.  Activation of Mitogen-Activated Protein Kinases after Transient Forebrain Ischemia in Gerbil Hippocampus , 2000, The Journal of Neuroscience.

[126]  Xiongwei Zhu,et al.  Activation of oncogenic pathways in degenerating neurons in Alzheimer disease , 2000, International Journal of Developmental Neuroscience.

[127]  Z. Gu,et al.  Extracellular signal-regulated kinase 1/2 activation in hippocampus after cerebral ischemia may not interfere with postischemic cell death , 2001, Brain Research.

[128]  R. Tanzi,et al.  Negative Regulation of the Sapk/Jnk Signaling Pathway by Presenilin 1 , 2001, The Journal of cell biology.

[129]  R. Burke,et al.  Expression of c‐fos, c‐jun, and N‐terminal kinase (JNK) in a Development Model of Induced Apoptotic Death in Neurons of the Substantia Nigra , 1999, Journal of neurochemistry.

[130]  K. Mielke,et al.  Activity and expression of JNK1, p38 and ERK kinases, c-Jun N-terminal phosphorylation, and c-jun promoter binding in the adult rat brain following kainate-induced seizures , 1999, Neuroscience.

[131]  P. Gass,et al.  Regionally selective stimulation of mitogen activated protein (MAP) kinase tyrosine phosphorylation after generalized seizures in the rat brain , 1993, Neuroscience Letters.

[132]  B. Ghetti,et al.  Activation of the JNK/p38 Pathway Occurs in Diseases Characterized by Tau Protein Pathology and Is Related to Tau Phosphorylation But Not to Apoptosis , 2001, Journal of neuropathology and experimental neurology.

[133]  G. Johnson,et al.  Modulation of tau phosphorylation and intracellular localization by cellular stress. , 2000, The Biochemical journal.

[134]  E. Schaefer,et al.  Activation of p38MAPK in Microglia After Ischemia , 1998, Journal of neurochemistry.

[135]  I. Ferrer,et al.  Phosphorylated mitogen-activated protein kinase (MAPK/ERK-P), protein kinase of 38 kDa (p38-P), stress-activated protein kinase (SAPK/JNK-P), and calcium/calmodulin-dependent kinase II (CaM kinase II) are differentially expressed in tau deposits in neurons and glial cells in tauopathies , 2001, Journal of Neural Transmission.

[136]  R. Balázs,et al.  β-Amyloid-(1–42) Impairs Activity-dependent cAMP-response Element-binding Protein Signaling in Neurons at Concentrations in Which Cell Survival Is Not Compromised* , 2001, The Journal of Biological Chemistry.

[137]  H. Itoh,et al.  Amyloid β protein precursor is involved in the growth of human colon carcinoma cell in vitro and in vivo , 2001 .

[138]  H. K. Sluss,et al.  Selective interaction of JNK protein kinase isoforms with transcription factors. , 1996, The EMBO journal.

[139]  Y. Oh,et al.  Two distinct mechanisms are involved in 6‐hydroxydopamine‐ and MPP+‐induced dopaminergic neuronal cell death: Role of caspases, ROS, and JNK , 1999, Journal of neuroscience research.

[140]  S. Vincent,et al.  Neurotransmitter regulation of MAP kinase signaling in striatal neurons in primary culture , 1998, Synapse.

[141]  J. Avruch,et al.  Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. , 2001, Physiological reviews.

[142]  P. Reiner,et al.  Regulation of Amyloid Precursor Protein Catabolism Involves the Mitogen-Activated Protein Kinase Signal Transduction Pathway , 1997, The Journal of Neuroscience.

[143]  F. Posas,et al.  A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress‐induced activation of the p38 and JNK pathways , 1997, The EMBO journal.

[144]  L. Greene,et al.  β‐Amyloid‐induced neuronal apoptosis requires c‐Jun N‐terminal kinase activation , 2001, Journal of neurochemistry.

[145]  M. Smith,et al.  Redox-active iron mediates amyloid-beta toxicity. , 2001, Free radical biology & medicine.

[146]  J. Baraban,et al.  Identification of p42 Mitogen‐Activated Protein Kinase as a Tyrosine Kinase Substrate Activated by Maximal Electroconvulsive Shock in Hippocampus , 1993, Journal of neurochemistry.

[147]  D. Troost,et al.  c‐Jun, JNK/SAPK Kinase and Transcription Factor NF-κB Are Selectively Activated in Astrocytes, but not Motor Neurons, in Amyotrophic Lateral Sclerosis , 1997, Journal of neuropathology and experimental neurology.

[148]  E. Klann,et al.  Long-Term Depression in the Adult Hippocampus In Vivo Involves Activation of Extracellular Signal-Regulated Kinase and Phosphorylation of Elk-1 , 2002, The Journal of Neuroscience.