H2o2 and 4-hydroxynonenal mediate amyloid β-induced neuronal apoptosis by activating jnks and p38mapk

Amyloid beta peptides (Abeta) may be neurotoxic during the progression of Alzheimer's disease by eliciting oxidative stress. Exposure of neuronally differentiated SK-N-BE cells to Abeta(25-35) fragment as well as to full-length Abeta(1-40) and Abeta(1-42) induces early and time-dependent generation of oxidative stress that has been evaluated by carefully monitoring generation of hydrogen peroxide (H(2)O(2)), 4-hydroxynonenal (HNE), thiobarbituric acid reactive substances (TBARS), and fluorescent chromolipids. Abeta treatment also results in the activation of c-Jun aminoterminal kinases (JNKs) and p38(MAPK) and is followed by characteristic nuclear changes of apoptosis as evaluated by DAPI staining and TUNEL technique. To reproduce the relationships between oxidative stress and Abeta apoptosis we found that only the simultaneous administration of HNE and H(2)O(2), at concentrations similar to those generated within the first 3 h of Abeta exposure, can fully mimic Abeta-dependent activation of JNKs and p38(MAPK) and occurrence of apoptosis. Antioxidants such as alpha-tocopherol and N-acetylcysteine prevent completely either neuronal apoptosis or activation of JNKs and p38(MAPK) elicited by Abeta or by simultaneous HNE and H(2)O(2) addition. Finally, direct evidence that activation of these kinases is required for cell death induced by Abeta has been obtained by pretreating cell with specific inhibitors of JNKs and p38(MAPK). These results suggest the existence of a sequence of events in Abeta-induced apoptosis involving simultaneous generation of HNE and H(2)O(2) and oxidative stress-dependent activation of JNKs and p38(MAPK).

[1]  I. Kang,et al.  Insulin-like growth factor-1 protects H9c2 cardiac myoblasts from oxidative stress-induced apoptosis via phosphatidylinositol 3-kinase and extracellular signal-regulated kinase pathways. , 2001, Life sciences.

[2]  J. Folch,et al.  A simple method for the isolation and purification of total lipides from animal tissues. , 1957, The Journal of biological chemistry.

[3]  Y. Christen,et al.  The ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by β‐amyloid , 2000 .

[4]  Douglas R. McDonald,et al.  β-Amyloid Fibrils Activate Parallel Mitogen-Activated Protein Kinase Pathways in Microglia and THP1 Monocytes , 1998, The Journal of Neuroscience.

[5]  A. Bruce.  β-Amyloid toxicity in organotypic cultures : protection by EUK-8, a synthetic catalytic free radical scavenger , 1996 .

[6]  W. Markesbery,et al.  Oxidative Alterations in Alzheimer's Disease , 1999, Brain pathology.

[7]  P. Baeuerle,et al.  Transcription factor NF-κB is activated in primary neurons by amyloid β peptides and in neurons surrounding early plaques from patients with Alzheimer disease , 1997 .

[8]  J. B. Hutchins,et al.  Bcl‐2 Protects Isolated Plasma and Mitochondrial Membranes Against Lipid Peroxidation Induced by Hydrogen Peroxide and Amyloid β‐Peptide , 1998, Journal of neurochemistry.

[9]  S. Friedman.  Molecular Regulation of Hepatic Fibrosis, an Integrated Cellular Response to Tissue Injury* , 2000, The Journal of Biological Chemistry.

[10]  H. Esterbauer,et al.  Possible involvement of the lipid-peroxidation product 4-hydroxynonenal in the formation of fluorescent chromolipids. , 1986, The Biochemical journal.

[11]  G. Poli,et al.  Separation and characterization of the aldehydic products of lipid peroxidation stimulated by ADP-Fe2+ in rat liver microsomes. , 1982, The Biochemical journal.

[12]  G. Poli,et al.  Oxidative damage and fibrogenesis. , 1997, Free radical biology & medicine.

[13]  N. Andrews,et al.  A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. , 1991, Nucleic acids research.

[14]  N. Bhat,et al.  Hydrogen Peroxide Activation of Multiple Mitogen‐Activated Protein Kinases in an Oligodendrocyte Cell Line , 1999, Journal of neurochemistry.

[15]  F. Zoccarato,et al.  Identification of an NADH plus iron dependent, Ca2+ activated hydrogen peroxide production in synaptosomes. , 1993, Biochimica et biophysica acta.

[16]  G. Cole,et al.  Vitamin E protects nerve cells from amyloid βprotein toxicity , 1992 .

[17]  E. Joe,et al.  Mitogen‐activated protein kinases activated by lipopolysaccharide and β‐amyloid in cultured rat microglia , 1998 .

[18]  C. Masters,et al.  Survival of Cultured Neurons from Amyloid Precursor Protein Knock-Out Mice against Alzheimer’s Amyloid-β Toxicity and Oxidative Stress , 1998, The Journal of Neuroscience.

[19]  Using and Understanding Medical Statistics. , 1987 .

[20]  T. Cruz,et al.  Reactive Oxygen Species Mediate Cytokine Activation of c-Jun NH2-terminal Kinases* , 1996, The Journal of Biological Chemistry.

[21]  M. Mattson,et al.  Evidence that 4-Hydroxynonenal Mediates Oxidative Stress-Induced Neuronal Apoptosis , 1997, The Journal of Neuroscience.

[22]  C. Culmsee,et al.  Neuronal apoptosis in Alzheimer ’ s disease , 2001 .

[23]  D. Selkoe.  Alzheimer's disease: genes, proteins, and therapy. , 2001, Physiological reviews.

[24]  J. B. Hutchins,et al.  Mitochondrial Manganese Superoxide Dismutase Prevents Neural Apoptosis and Reduces Ischemic Brain Injury: Suppression of Peroxynitrite Production, Lipid Peroxidation, and Mitochondrial Dysfunction , 1998, The Journal of Neuroscience.

[25]  W. Rosenblum.  The presence, origin, and significance of A beta peptide in the cell bodies of neurons. , 1999, Journal of neuropathology and experimental neurology.

[26]  A. Fagan,et al.  Astrocyte lipoproteins, effects of apoE on neuronal function, and role of apoE in amyloid‐β deposition in vivo , 2000, Microscopy research and technique.

[27]  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.

[28]  E. Yavin,et al.  Biphasic modulation of protein kinase C and enhanced cell toxicity by amyloid beta peptide and anoxia in neuronal cultures , 2001, Journal of neurochemistry.

[29]  M. Tabaton,et al.  Amyloid‐β Deposition in Alzheimer Transgenic Mice Is Associated with Oxidative Stress , 1998, Journal of neurochemistry.

[30]  L. Rubin,et al.  Phosphorylation of c-Jun Is Necessary for Apoptosis Induced by Survival Signal Withdrawal in Cerebellar Granule Neurons , 1998, The Journal of Neuroscience.

[31]  Y. Christen,et al.  Oxidative stress and Alzheimer disease. , 2000, The American journal of clinical nutrition.

[32]  K. Heidenreich,et al.  Apoptosis Induced by Withdrawal of Trophic Factors Is Mediated by p38 Mitogen-activated Protein Kinase* , 1997, The Journal of Biological Chemistry.

[33]  G. Bellomo,et al.  HNE interacts directly with JNK isoforms in human hepatic stellate cells. , 1998, The Journal of clinical investigation.

[34]  Y. Soh,et al.  Selective activation of the c-Jun N-terminal protein kinase pathway during 4-hydroxynonenal-induced apoptosis of PC12 cells. , 2000, Molecular pharmacology.

[35]  S. Ben‐Sasson,et al.  Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation , 1992, The Journal of cell biology.

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

[37]  J. Pié,et al.  Apoptosis of PC12 cells by 4-hydroxy-2-nonenal is mediated through selective activation of the c-Jun N-terminal protein kinase pathway. , 2001, Chemico-biological interactions.

[38]  C. Behl.  Alzheimer's disease and oxidative stress: implications for novel therapeutic approaches , 1999, Progress in Neurobiology.

[39]  M. Mattson,et al.  A Role for 4‐Hydroxynonenal, an Aldehydic Product of Lipid Peroxidation, in Disruption of Ion Homeostasis and Neuronal Death Induced by Amyloid β‐Peptide , 1997, Journal of neurochemistry.

[40]  H. Esterbauer,et al.  Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. , 1991, Free radical biology & medicine.

[41]  M. Baudry,et al.  beta-Amyloid toxicity in organotypic hippocampal cultures: protection by EUK-8, a synthetic catalytic free radical scavenger. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[42]  J. Kalinich,et al.  4-Hydroxynonenal, an end-product of lipid peroxidation, induces apoptosis in human leukemic T- and B-cell lines , 2000, Free radical research.

[43]  C. Kunsch,et al.  Oxidative stress as a regulator of gene expression in the vasculature. , 1999, Circulation research.

[44]  M. Parola,et al.  NT2 neurons, a classical model for Alzheimer's disease, are highly susceptible to oxidative stress , 2000, Neuroreport.

[45]  C. Behl,et al.  Hydrogen peroxide mediates amyloid β protein toxicity , 1994, Cell.

[46]  K. Roth.  Caspases, Apoptosis, and Alzheimer Disease: Causation, Correlation, and Confusion , 2001, Journal of neuropathology and experimental neurology.

[47]  D. Green,et al.  Withdrawal of Survival Factors Results in Activation of the JNK Pathway in Neuronal Cells Leading to Fas Ligand Induction and Cell Death , 1999, Molecular and Cellular Biology.

[48]  Jonathan A. Cooper,et al.  Rho family members: Activators of MAP kinase cascades , 1995, Cell.

[49]  M. Mattson,et al.  β-Amyloid Peptide Free Radical Fragments Initiate Synaptosomal Lipoperoxidation in a Sequence-Specific Fashion: Implications to Alzheimer′s Disease , 1994 .

[50]  M. Mattson,et al.  The Lipid Peroxidation Product 4‐Hydroxy‐2,3‐Nonenal Increases AP‐1‐Binding Activity Through Caspase Activation in Neurons , 2000, Journal of neurochemistry.

[51]  Yoshimasa Nakamura,et al.  Activation of Stress Signaling Pathways by the End Product of Lipid Peroxidation , 1999, The Journal of Biological Chemistry.

[52]  A. LeBlanc,et al.  Amyloid β Peptide of Alzheimer’s Disease Downregulates Bcl-2 and Upregulates Bax Expression in Human Neurons , 1996, The Journal of Neuroscience.

[53]  Hui-zhen Wang,et al.  Oxidative Preconditioning and Apoptosis in L-cells , 2001, The Journal of Biological Chemistry.

[54]  B. Rovin,et al.  Interleukin-1β Induction of Mitogen-activated Protein Kinases in Human Mesangial Cells , 1997, The Journal of Biological Chemistry.

[55]  B. Volk,et al.  Inhibition of NF-kappaB potentiates amyloid beta-mediated neuronal apoptosis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[56]  M. Behrens,et al.  Prevention of neuronal apoptosis by phorbol ester-induced activation of protein kinase C: blockade of p38 mitogen-activated protein kinase , 1999, Neuroscience.

[57]  Xiantao Wang,et al.  Dopamine Induces Apoptosis through an Oxidation-involved SAPK/JNK Activation Pathway* , 1998, The Journal of Biological Chemistry.

[58]  M. Sortino,et al.  Relative Contribution of Different Receptor Subtypes in the Response of Neuroblastoma Cells to Tumor Necrosis Factor‐α , 2000, Journal of neurochemistry.

[59]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.