Activation of MKK6, an upstream activator of p38, in Alzheimer's disease

Mitogen‐activated protein kinase (MAPK) p38 has been implicated in the pathogenesis of Alzheimer's disease, but the upstream cascade leading to p38 activation has not been elucidated in the disease. In the present study, we focused on mitogen‐activated protein kinase kinase 6 (MKK6), one of the upstream activators of p38 MAPK. We found that MKK6 was not only increased but also specifically associated with granular structures in the susceptible neurons in the hippocampus and cortex of Alzheimer's disease patients, but was only weakly diffuse in the cytoplasm in neurons in control cases. Immunoblot analysis demonstrated a significant increase of MKK6 level in Alzheimer's disease compared with age‐matched controls. In this regard, in hippocampal and cortical regions of individuals with Alzheimer's disease, the activated phospho‐MKK6 was localized exclusively in association with pathological alterations including neurofibrillary tangles, senile plaques, neuropil threads and granular structures, overlapping with activated p38 MAPK suggesting both a functional and mechanic link. By immunoblot analysis, phospho‐MKK6 is also significantly increased in AD compared with control cases. Together, these findings lend further credence to the notion that the p38 MAPK pathway is dysregulated in Alzheimer's disease and also indicates an active role for this pathway in disease pathogenesis.

[1]  R. Bucala,et al.  Advanced glycation end products contribute to amyloidosis in Alzheimer disease. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[2]  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.

[3]  N. Robakis,et al.  Immunohistochemical evidence of antioxidant stress in Alzheimer's disease , 1992 .

[4]  J. Avruch,et al.  Sounding the Alarm: Protein Kinase Cascades Activated by Stress and Inflammation* , 1996, The Journal of Biological Chemistry.

[5]  S. M. Sumi,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) , 1991, Neurology.

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

[7]  Jiahuai Han,et al.  Characterization of the Structure and Function of a Novel MAP Kinase Kinase (MKK6) (*) , 1996, The Journal of Biological Chemistry.

[8]  Mark A. Smith,et al.  Early AGEing and Alzheimer's , 1995, Nature.

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

[10]  Xiaomin Wang,et al.  Inhibitors of p38 MAP kinase increase the survival of transplanted dopamine neurons , 2001, Brain Research.

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

[12]  Xiongwei Zhu,et al.  Cyclin' toward dementia , 2000, Journal of neuroscience research.

[13]  S. Lipton,et al.  Role of p38 Mitogen-Activated Protein Kinase in Axotomy-Induced Apoptosis of Rat Retinal Ganglion Cells , 2000, The Journal of Neuroscience.

[14]  M. Smith,et al.  Advanced Maillard reaction end products are associated with Alzheimer disease pathology , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[15]  G. Perry,et al.  Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome. , 2000, Journal of neuropathology and experimental neurology.

[16]  J. Zweier,et al.  Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid β-peptide , 1995, Nature Medicine.

[17]  G. Perry,et al.  Advanced Maillard reaction end products are associated with Alzheimer disease pathology. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[18]  E. Stopa,et al.  Expression of heme oxygenase‐1 in the senescent and alzheimer‐diseased brain , 1995, Annals of neurology.

[19]  E. Nishida,et al.  Activation of the protein kinase p38 in the spindle assembly checkpoint and mitotic arrest. , 1998, Science.

[20]  J. Pouysségur,et al.  Cyclin D1 Expression Is Regulated Positively by the p42/p44MAPK and Negatively by the p38/HOGMAPK Pathway* , 1996, The Journal of Biological Chemistry.

[21]  G. Perry,et al.  Do neurons have a choice in death? , 2001, The American journal of pathology.

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

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

[24]  Z. Khachaturian.  Diagnosis of Alzheimer's disease. , 1985, Archives of neurology.

[25]  B. Yankner,et al.  β-Amyloid fibrils induce tau phosphorylation and loss of microtubule binding , 1995, Neuron.

[26]  P. Maher,et al.  p38 Mitogen-activated Protein Kinase Activation Is Required for Fibroblast Growth Factor-2-stimulated Cell Proliferation but Not Differentiation* , 1999, The Journal of Biological Chemistry.

[27]  George Perry,et al.  RNA Oxidation Is a Prominent Feature of Vulnerable Neurons in Alzheimer’s Disease , 1999, The Journal of Neuroscience.

[28]  D. Perl,et al.  Evidence of neuronal oxidative damage in Alzheimer's disease. , 1996, The American journal of pathology.

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

[30]  Jiahuai Han,et al.  Involvement of the MKK6-p38γ Cascade in γ-Radiation-Induced Cell Cycle Arrest , 2000, Molecular and Cellular Biology.

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

[32]  C. Filley.  Diagnosis of Alzheimer's disease. , 1988, Colorado medicine.

[33]  Joseph S. Beckman,et al.  Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease , 1997, The Journal of Neuroscience.

[34]  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.

[35]  N. Nath,et al.  Regulation of Rb and E2F by signal transduction cascades: divergent effects of JNK1 and p38 kinases , 1999, The EMBO journal.

[36]  R N Kalaria,et al.  Induction of Heme Oxygenase‐1 mRNA and Protein in Neocortex and Cerebral Vessels in Alzheimer's Disease , 1995, Journal of neurochemistry.

[37]  G. Perry,et al.  Neuronal Oxidative Stress Precedes Amyloid‐β Deposition in Down Syndrome , 2000 .

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

[39]  K. Noguchi,et al.  Differential role of the JNK and p38 MAPK pathway in c-Myc- and s-Myc-mediated apoptosis. , 2000, Biochemical and biophysical research communications.

[40]  L. Zon,et al.  Cdc42Hs, but Not Rac1, Inhibits Serum-stimulated Cell Cycle Progression at G1/S through a Mechanism Requiring p38/RK* , 1997, The Journal of Biological Chemistry.

[41]  D. Zechner,et al.  A Role for the p38 Mitogen-activated Protein Kinase Pathway in Myocardial Cell Growth, Sarcomeric Organization, and Cardiac-specific Gene Expression , 1997, The Journal of cell biology.

[42]  P. Cohen,et al.  The search for physiological substrates of MAP and SAP kinases in mammalian cells. , 1997, Trends in cell biology.

[43]  E. Krebs,et al.  Caspase‐mediated activation and induction of apoptosis by the mammalian Ste20‐like kinase Mst1 , 1998, The EMBO journal.

[44]  G. Perry,et al.  Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer's disease. , 1994, The American journal of pathology.

[45]  J. Caboche,et al.  Ceramide‐induced apoptosis in cortical neurons is mediated by an increase in p38 phosphorylation and not by the decrease in ERK phosphorylation , 2001, The European journal of neuroscience.

[46]  Xiongwei Zhu,et al.  Abortive apoptosis in Alzheimer's disease , 2001, Acta Neuropathologica.

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

[48]  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.

[49]  T. Montine,et al.  4‐Hydroxy‐2‐Nonenal Pyrrole Adducts in Human Neurodegenerative Disease , 1997, Journal of neuropathology and experimental neurology.

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

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

[52]  INTERNATIONAL SOCIETY FOR NEUROCHEMISTRY , 1976 .

[53]  Mark A. Smith,et al.  Carbonyl‐Related Posttranslational Modification of Neurofilament Protein in the Neurofibrillary Pathology of Alzheimer's Disease , 1995, Journal of neurochemistry.

[54]  M. Smith,et al.  Early glycoxidation damage in brains from Down's syndrome. , 1998, Biochemical and biophysical research communications.

[55]  C. Marshall,et al.  Cooperation of p38 and Extracellular Signal-regulated Kinase Mitogen-activated Protein Kinase Pathways during Granulocyte Colony-stimulating Factor-induced Hemopoietic Cell Proliferation* , 1999, The Journal of Biological Chemistry.

[56]  Mark A. Smith,et al.  4‐Hydroxynonenal‐Derived Advanced Lipid Peroxidation End Products Are Increased in Alzheimer's Disease , 1997, Journal of neurochemistry.

[57]  E. Nishida,et al.  Fas Induces Cytoplasmic Apoptotic Responses and Activation of the MKK7-JNK/SAPK and MKK6-p38 Pathways Independent of CPP32-like Proteases , 1997, The Journal of cell biology.

[58]  C. W. Scott,et al.  Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. , 1994, Proceedings of the National Academy of Sciences of the United States of America.