Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Neurosci. 21 (19): 7551-7560

Copyright © 2001 by the Society for Neuroscience.

The Journal of Neuroscience, October 1, 2001, 21(19):7551-7560

beta -Amyloid Induces Neuronal Apoptosis Via a Mechanism that Involves the c-Jun N-Terminal Kinase Pathway and the Induction of Fas Ligand

Yoshiyuki Morishima1, Yukiko Gotoh1, Janine Zieg1, Tamera Barrett2, Hiromichi Takano3, Richard Flavell4, Roger J. Davis2, Yasufumi Shirasaki3, and Michael E. Greenberg1

1 Division of Neuroscience, Children's Hospital, and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, 2 Howard Hughes Medical Institute, Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, 3 New Products Research Laboratories III, Daiichi Pharmaceutical Co., Ltd., Tokyo 134-8636, Japan, and 4 Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510

Elevated levels of beta -Amyloid (Abeta ) are present in the brains of individuals with either the sporadic or familial form of Alzheimer's disease (AD), and the deposition of Abeta within the senile plaques that are a hallmark of AD is thought to be a primary cause of the cognitive dysfunction that occurs in AD. Recent evidence suggests that Abeta induces neuronal apoptosis in the brain and in primary neuronal cultures, and that this Abeta -induced neuronal death may be responsible in part for the cognitive decline found in AD patients. In this study we have characterized one mechanism by which Abeta induces neuronal death. We found that in cortical neurons exposed to Abeta , activated c-Jun N-terminal kinase (JNK) is required for the phosphorylation and activation of the c-Jun transcription factor, which in turn stimulates the transcription of several key target genes, including the death inducer Fas ligand. The binding of Fas ligand to its receptor Fas then induces a cascade of events that lead to caspase activation and ultimately cell death. By analyzing the effects of mutations in each of the components of the JNK-c-Jun-Fas ligand-Fas pathway, we demonstrate that this pathway plays a critical role in mediating Abeta -induced death of cultured neurons. These findings raise the possibility that the JNK pathway may also contribute to Abeta -dependent death in AD patients.

Key words: Alzheimer's disease; beta -amyloid; c-Jun N-terminal kinase; JNK; c-Jun; Fas; Fas ligand; apoptosis; neuronal cell death

Copyright © 2001 Society for Neuroscience  0270-6474/01/21197551-10$05.00/0

FAIM-L Is an IAP-Binding Protein That Inhibits XIAP Ubiquitinylation and Protects from Fas-Induced Apoptosis.
R. S. Moubarak, L. Planells-Ferrer, J. Urresti, S. Reix, M. F. Segura, P. Carriba, F. Marques-Fernandez, C. Sole, N. Llecha-Cano, J. Lopez-Soriano, et al. (2013)
J. Neurosci. 33, 19262-19275
   Abstract »    Full Text »    PDF »
Dual leucine zipper kinase is required for excitotoxicity-induced neuronal degeneration.
C. D. Pozniak, A. Sengupta Ghosh, A. Gogineni, J. E. Hanson, S.-H. Lee, J. L. Larson, H. Solanoy, D. Bustos, H. Li, H. Ngu, et al. (2013)
J. Exp. Med. 210, 2553-2567
   Abstract »    Full Text »    PDF »
De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer's disease.
H.-K. A. Wong, T. Veremeyko, N. Patel, C. A. Lemere, D. M. Walsh, C. Esau, C. Vanderburg, and A. M. Krichevsky (2013)
Hum. Mol. Genet. 22, 3077-3092
   Abstract »    Full Text »    PDF »
Serrapeptase and nattokinase intervention for relieving Alzheimer's disease pathophysiology in rat model.
N. Fadl, H. Ahmed, H. Booles, and A. Sayed (2013)
Human and Experimental Toxicology 32, 721-735
   Abstract »    Full Text »    PDF »
Molecular chaperones protect against JNK- and Nmnat-regulated axon degeneration in Drosophila.
A. Rallis, B. Lu, and J. Ng (2013)
J. Cell Sci. 126, 838-849
   Abstract »    Full Text »    PDF »
Acupuncture improves cognitive deficits and increases neuron density of the hippocampus in middle-aged SAMP8 mice.
G. Li, X. Zhang, H. Cheng, X. Shang, H. Xie, X. Zhang, J. Yu, and J. Han (2012)
Acupunct Med 30, 339-345
   Abstract »    Full Text »    PDF »
Enzyme Kinetics and Interaction Studies for Human JNK1{beta}1 and Substrates Activating Transcription Factor 2 (ATF2) and c-Jun N-terminal kinase (c-Jun).
M. Figuera-Losada and P. V. LoGrasso (2012)
J. Biol. Chem. 287, 13291-13302
   Abstract »    Full Text »    PDF »
c-Jun N-terminal Kinase Regulates Soluble A{beta} Oligomers and Cognitive Impairment in AD Mouse Model.
A. Sclip, X. Antoniou, A. Colombo, G. G. Camici, L. Pozzi, D. Cardinetti, M. Feligioni, P. Veglianese, F. H. Bahlmann, L. Cervo, et al. (2011)
J. Biol. Chem. 286, 43871-43880
   Abstract »    Full Text »    PDF »
The Loss of c-Jun N-Terminal Protein Kinase Activity Prevents the Amyloidogenic Cleavage of Amyloid Precursor Protein and the Formation of Amyloid Plaques In Vivo.
S. Mazzitelli, P. Xu, I. Ferrer, R. J. Davis, and C. Tournier (2011)
J. Neurosci. 31, 16969-16976
   Abstract »    Full Text »    PDF »
Hippocampal c-Jun-N-Terminal Kinases Serve as Negative Regulators of Associative Learning.
T. Sherrin, T. Blank, C. Hippel, M. Rayner, R. J. Davis, and C. Todorovic (2010)
J. Neurosci. 30, 13348-13361
   Abstract »    Full Text »    PDF »
Microglial Receptor for Advanced Glycation End Product-Dependent Signal Pathway Drives {beta}-Amyloid-Induced Synaptic Depression and Long-Term Depression Impairment in Entorhinal Cortex.
N. Origlia, C. Bonadonna, A. Rosellini, E. Leznik, O. Arancio, S. S. Yan, and L. Domenici (2010)
J. Neurosci. 30, 11414-11425
   Abstract »    Full Text »    PDF »
The p75 Neurotrophin Receptor Promotes Amyloid-{beta}(1-42)-Induced Neuritic Dystrophy In Vitro and In Vivo.
J. K. Knowles, J. Rajadas, T.-V. V. Nguyen, T. Yang, M. C. LeMieux, L. Vander Griend, C. Ishikawa, S. M. Massa, T. Wyss-Coray, and F. M. Longo (2009)
J. Neurosci. 29, 10627-10637
   Abstract »    Full Text »    PDF »
Opposing Roles for ATF2 and c-Fos in c-Jun-Mediated Neuronal Apoptosis.
Z. Yuan, S. Gong, J. Luo, Z. Zheng, B. Song, S. Ma, J. Guo, C. Hu, G. Thiel, C. Vinson, et al. (2009)
Mol. Cell. Biol. 29, 2431-2442
   Abstract »    Full Text »    PDF »
Tumor Necrosis Factor-{alpha}-elicited Stimulation of {gamma}-Secretase Is Mediated by c-Jun N-terminal Kinase-dependent Phosphorylation of Presenilin and Nicastrin.
L.-H. Kuo, M.-K. Hu, W.-M. Hsu, Y.-T. Tung, B.-J. Wang, W.-W. Tsai, C.-T. Yen, and Y.-F. Liao (2008)
Mol. Biol. Cell 19, 4201-4212
   Abstract »    Full Text »    PDF »
All JNKs Can Kill, but Nuclear Localization Is Critical for Neuronal Death.
B. Bjorkblom, J. C. Vainio, V. Hongisto, T. Herdegen, M. J. Courtney, and E. T. Coffey (2008)
J. Biol. Chem. 283, 19704-19713
   Abstract »    Full Text »    PDF »
Molecular and cellular aspects of protein misfolding and disease.
E. Herczenik and M. F. B. G. Gebbink (2008)
FASEB J 22, 2115-2133
   Abstract »    Full Text »    PDF »
The {beta}-Arrestin-2 Scaffold Protein Promotes c-Jun N-terminal Kinase-3 Activation by Binding to Its Nonconserved N Terminus.
C. Guo and A. J. Whitmarsh (2008)
J. Biol. Chem. 283, 15903-15911
   Abstract »    Full Text »    PDF »
Endophilin I Expression Is Increased in the Brains of Alzheimer Disease Patients.
Y. Ren, H. W. Xu, F. Davey, M. Taylor, J. Aiton, P. Coote, F. Fang, J. Yao, D. Chen, J. X. Chen, et al. (2008)
J. Biol. Chem. 283, 5685-5691
   Abstract »    Full Text »    PDF »
The Cell-Selective Neurotoxicity of the Alzheimer's A Peptide Is Determined by Surface Phosphatidylserine and Cytosolic ATP Levels. Membrane Binding Is Required for A Toxicity.
O. Simakova and N. J. Arispe (2007)
J. Neurosci. 27, 13719-13729
   Abstract »    Full Text »    PDF »
Concentration Dependence of the Mechanisms of Tributyltin-Induced Apoptosis.
Y. Nakatsu, Y. Kotake, and S. Ohta (2007)
Toxicol. Sci. 97, 438-447
   Abstract »    Full Text »    PDF »
Connecting TNF-{alpha} Signaling Pathways to iNOS Expression in a Mouse Model of Alzheimer's Disease: Relevance for the Behavioral and Synaptic Deficits Induced by Amyloid {beta} Protein.
R. Medeiros, R. D. S. Prediger, G. F. Passos, P. Pandolfo, F. S. Duarte, J. L. Franco, A. L. Dafre, G. Di Giunta, C. P. Figueiredo, R. N. Takahashi, et al. (2007)
J. Neurosci. 27, 5394-5404
   Abstract »    Full Text »    PDF »
Estrogen Regulates Bcl-w and Bim Expression: Role in Protection against {beta}-Amyloid Peptide-Induced Neuronal Death.
M. Yao, T.-V. V. Nguyen, and C. J. Pike (2007)
J. Neurosci. 27, 1422-1433
   Abstract »    Full Text »    PDF »
Neuronal Pentraxin 1 Contributes to the Neuronal Damage Evoked by Amyloid-{beta} and Is Overexpressed in Dystrophic Neurites in Alzheimer's Brain.
M. A. Abad, M. Enguita, N. DeGregorio-Rocasolano, I. Ferrer, and R. Trullas (2006)
J. Neurosci. 26, 12735-12747
   Abstract »    Full Text »    PDF »
The Yeast Prion Ure2p Native-like Assemblies Are Toxic to Mammalian Cells Regardless of Their Aggregation State.
L. Pieri, M. Bucciantini, D. Nosi, L. Formigli, J. Savistchenko, R. Melki, and M. Stefani (2006)
J. Biol. Chem. 281, 15337-15344
   Abstract »    Full Text »    PDF »
System Xc- and apolipoprotein E expressed by microglia have opposite effects on the neurotoxicity of amyloid-beta peptide 1-40..
S. Qin, C. Colin, I. Hinners, A. Gervais, C. Cheret, and M. Mallat (2006)
J. Neurosci. 26, 3345-3356
   Abstract »    Full Text »    PDF »
Intraneuronal {beta}-Amyloid Expression Downregulates the Akt Survival Pathway and Blunts the Stress Response.
J. Magrane, K. M. Rosen, R. C. Smith, K. Walsh, G. K. Gouras, and H. W. Querfurth (2005)
J. Neurosci. 25, 10960-10969
   Abstract »    Full Text »    PDF »
Insights into the molecular basis of the differing susceptibility of varying cell types to the toxicity of amyloid aggregates.
C. Cecchi, S. Baglioni, C. Fiorillo, A. Pensalfini, G. Liguri, D. Nosi, S. Rigacci, M. Bucciantini, and M. Stefani (2005)
J. Cell Sci. 118, 3459-3470
   Abstract »    Full Text »    PDF »
Akt-dependent Expression of NAIP-1 Protects Neurons against Amyloid-{beta} Toxicity.
S. Lesne, C. Gabriel, D. A. Nelson, E. White, E. T. MacKenzie, D. Vivien, and A. Buisson (2005)
J. Biol. Chem. 280, 24941-24947
   Abstract »    Full Text »    PDF »
Sex, Hormones, and Alzheimer's Disease.
L. W. Baum (2005)
J Gerontol A Biol Sci Med Sci 60, 736-743
   Abstract »    Full Text »    PDF »
Glutathione S-Transferase P1 *C Allelic Variant Increases Susceptibility for Late-Onset Alzheimer Disease: Association Study and Relationship with Apolipoprotein E {epsilon}4 Allele.
S. Bernardini, L. Bellincampi, S. Ballerini, G. Federici, R. Iori, A. Trequattrini, F. Ciappi, F. Baldinetti, P. Bossu, C. Caltagirone, et al. (2005)
Clin. Chem. 51, 944-951
   Abstract »    Full Text »    PDF »
Amyloid-{beta} neurotoxicity is mediated by FISH adapter protein and ADAM12 metalloprotease activity.
N. L. Malinin, S. Wright, P. Seubert, D. Schenk, and I. Griswold-Prenner (2005)
PNAS 102, 3058-3063
   Abstract »    Full Text »    PDF »
Nucleation-Dependent Polymerization Is an Essential Component of Amyloid-Mediated Neuronal Cell Death.
M. Wogulis, S. Wright, D. Cunningham, T. Chilcote, K. Powell, and R. E. Rydel (2005)
J. Neurosci. 25, 1071-1080
   Abstract »    Full Text »    PDF »
{beta}-Amyloid-Induced Neuronal Apoptosis Involves c-Jun N-Terminal Kinase-Dependent Downregulation of Bcl-w.
M. Yao, T.-V. V. Nguyen, and C. J. Pike (2005)
J. Neurosci. 25, 1149-1158
   Abstract »    Full Text »    PDF »
c-Jun N-terminal Kinase 3 Deficiency Protects Neurons from Axotomy-induced Death in Vivo through Mechanisms Independent of c-Jun Phosphorylation.
E. Keramaris, J. L. Vanderluit, M. Bahadori, K. Mousavi, R. J. Davis, R. Flavell, R. S. Slack, and D. S. Park (2005)
J. Biol. Chem. 280, 1132-1141
   Abstract »    Full Text »    PDF »
JNK2 Translocates to the Mitochondria and Mediates Cytochrome c Release in PC12 Cells in Response to 6-Hydroxydopamine.
S. Eminel, A. Klettner, L. Roemer, T. Herdegen, and V. Waetzig (2004)
J. Biol. Chem. 279, 55385-55392
   Abstract »    Full Text »    PDF »
Distinct Requirements for p38{alpha} and c-Jun N-terminal Kinase Stress-activated Protein Kinases in Different Forms of Apoptotic Neuronal Death.
J. Cao, M. M. Semenova, V. T. Solovyan, J. Han, E. T. Coffey, and M. J. Courtney (2004)
J. Biol. Chem. 279, 35903-35913
   Abstract »    Full Text »    PDF »
Down-regulation of WW Domain-containing Oxidoreductase Induces Tau Phosphorylation in Vitro: A POTENTIAL ROLE IN ALZHEIMER'S DISEASE.
C.-I Sze, M. Su, S. Pugazhenthi, P. Jambal, L.-J. Hsu, J. Heath, L. Schultz, and N.-S. Chang (2004)
J. Biol. Chem. 279, 30498-30506
   Abstract »    Full Text »    PDF »
Block of Long-Term Potentiation by Naturally Secreted and Synthetic Amyloid {beta}-Peptide in Hippocampal Slices Is Mediated via Activation of the Kinases c-Jun N-Terminal Kinase, Cyclin-Dependent Kinase 5, and p38 Mitogen-Activated Protein Kinase as well as Metabotropic Glutamate Receptor Type 5.
Q. Wang, D. M. Walsh, M. J. Rowan, D. J. Selkoe, and R. Anwyl (2004)
J. Neurosci. 24, 3370-3378
   Abstract »    Full Text »    PDF »
Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer's disease brain and hippocampal neurons.
K. Del Villar and C. A. Miller (2004)
PNAS 101, 4210-4215
   Abstract »    Full Text »    PDF »
Regulation of Dopaminergic Loss by Fas in a 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson's Disease.
S. Hayley, S. J. Crocker, P. D. Smith, T. Shree, V. Jackson-Lewis, S. Przedborski, M. Mount, R. Slack, H. Anisman, and D. S. Park (2004)
J. Neurosci. 24, 2045-2053
   Abstract »    Full Text »    PDF »
Tumor Necrosis Factor Death Receptor Signaling Cascade Is Required for Amyloid-{beta} Protein-Induced Neuron Death.
R. Li, L. Yang, K. Lindholm, Y. Konishi, X. Yue, H. Hampel, D. Zhang, and Y. Shen (2004)
J. Neurosci. 24, 1760-1771
   Abstract »    Full Text »    PDF »
JNK-dependent Phosphorylation of c-Jun on Serine 63 Mediates Nitric Oxide-induced Apoptosis of Neuroblastoma Cells.
L. Li, Z. Feng, and A. G. Porter (2004)
J. Biol. Chem. 279, 4058-4065
   Abstract »    Full Text »    PDF »
Fas/Tumor Necrosis Factor Receptor Death Signaling Is Required for Axotomy-Induced Death of Motoneurons In Vivo.
G. Ugolini, C. Raoul, A. Ferri, C. Haenggeli, Y. Yamamoto, D. Salaun, C. E. Henderson, A. C. Kato, B. Pettmann, and A.-O. Hueber (2003)
J. Neurosci. 23, 8526-8531
   Abstract »    Full Text »    PDF »
Differential activation of the c-Jun N-terminal kinase/stress-activated protein kinase and p38 mitogen-activated protein kinase signal transduction pathways in the mouse brain upon infection with neurovirulent influenza A virus.
I. Mori, F. Goshima, T. Koshizuka, N. Koide, T. Sugiyama, T. Yoshida, T. Yokochi, Y. Nishiyama, and Y. Kimura (2003)
J. Gen. Virol. 84, 2401-2408
   Abstract »    Full Text »    PDF »
Lithium Blocks the c-Jun Stress Response and Protects Neurons via Its Action on Glycogen Synthase Kinase 3.
V. Hongisto, N. Smeds, S. Brecht, T. Herdegen, M. J. Courtney, and E. T. Coffey (2003)
Mol. Cell. Biol. 23, 6027-6036
   Abstract »    Full Text »    PDF »
Neurotoxic Mechanisms Caused by the Alzheimer's Disease-linked Swedish Amyloid Precursor Protein Mutation: OXIDATIVE STRESS, CASPASES, AND THE JNK PATHWAY.
C. A. Marques, U. Keil, A. Bonert, B. Steiner, C. Haass, W. E. Muller, and A. Eckert (2003)
J. Biol. Chem. 278, 28294-28302
   Abstract »    Full Text »    PDF »
Activation of the c-Jun N-terminal Kinase Signaling Cascade Mediates the Effect of Amyloid-{beta} on Long Term Potentiation and Cell Death in Hippocampus: A ROLE FOR INTERLEUKIN-1{beta}?.
A. M. Minogue, A. W. Schmid, M. P. Fogarty, A. C. Moore, V. A. Campbell, C. E. Herron, and M. A. Lynch (2003)
J. Biol. Chem. 278, 27971-27980
   Abstract »    Full Text »    PDF »
Trafficking of signaling modules by kinesin motors.
B. J. Schnapp (2003)
J. Cell Sci. 116, 2125-2135
   Abstract »    Full Text »    PDF »
Activation of JNK by Vanadate Induces a Fas-associated Death Domain (FADD)-dependent Death of Cerebellar Granule Progenitors in Vitro.
J. Luo, Y. Sun, H. Lin, Y. Qian, Z. Li, S. S. Leonard, C. Huang, and X. Shi (2003)
J. Biol. Chem. 278, 4542-4551
   Abstract »    Full Text »    PDF »
Apoptotic Neuronal Cell Death Induced by the Non-fibrillar Amyloid-beta Peptide Proceeds through an Early Reactive Oxygen Species-dependent Cytoskeleton Perturbation.
I. Sponne, A. Fifre, B. Drouet, C. Klein, V. Koziel, M. Pincon-Raymond, J.-L. Olivier, J. Chambaz, and T. Pillot (2003)
J. Biol. Chem. 278, 3437-3445
   Abstract »    Full Text »    PDF »
The Herpes Simplex Virus Type 2 R1 Protein Kinase (ICP10 PK) Functions as a Dominant Regulator of Apoptosis in Hippocampal Neurons Involving Activation of the ERK Survival Pathway and Upregulation of the Antiapoptotic Protein Bag-1.
D. Perkins, E. F. R. Pereira, and L. Aurelian (2003)
J. Virol. 77, 1292-1305
   Abstract »    Full Text »    PDF »
A Single c-Jun N-terminal Kinase Isoform (JNK3-p54) Is an Effector in Both Neuronal Differentiation and Cell Death.
V. Waetzig and T. Herdegen (2003)
J. Biol. Chem. 278, 567-572
   Abstract »    Full Text »    PDF »
Confirmation by FRET in individual living cells of the absence of significant amyloid {beta}-mediated caspase 8 activation.
R. Onuki, A. Nagasaki, H. Kawasaki, T. Baba, T. Q. P. Uyeda, and K. Taira (2002)
PNAS 99, 14716-14721
   Abstract »    Full Text »    PDF »
Aberrant Tau Phosphorylation by Glycogen Synthase Kinase-3beta and JNK3 Induces Oligomeric Tau Fibrils in COS-7 Cells.
S. Sato, Y. Tatebayashi, T. Akagi, D.-H. Chui, M. Murayama, T. Miyasaka, E. Planel, K. Tanemura, X. Sun, T. Hashikawa, et al. (2002)
J. Biol. Chem. 277, 42060-42065
   Abstract »    Full Text »    PDF »
Olfactory receptor neurons prevent dissemination of neurovirulent influenza A virus into the brain by undergoing virus-induced apoptosis.
I. Mori, F. Goshima, Y. Imai, S. Kohsaka, T. Sugiyama, T. Yoshida, T. Yokochi, Y. Nishiyama, and Y. Kimura (2002)
J. Gen. Virol. 83, 2109-2116
   Abstract »    Full Text »    PDF »
Apolipoprotein E4 Potentiates Amyloid beta Peptide-induced Lysosomal Leakage and Apoptosis in Neuronal Cells.
Z.-S. Ji, R. D. Miranda, Y. M. Newhouse, K. H. Weisgraber, Y. Huang, and R. W. Mahley (2002)
J. Biol. Chem. 277, 21821-21828
   Abstract »    Full Text »    PDF »
Signaling Events in Amyloid beta -Peptide-induced Neuronal Death and Insulin-like Growth Factor I Protection.
W. Wei, X. Wang, and J. W. Kusiak (2002)
J. Biol. Chem. 277, 17649-17656
   Abstract »    Full Text »    PDF »
Activation of c-Jun N-Terminal Kinase and p38 in an Alzheimer's Disease Model Is Associated with Amyloid Deposition.
M. J. Savage, Y.-G. Lin, J. R. Ciallella, D. G. Flood, and R. W. Scott (2002)
J. Neurosci. 22, 3376-3385
   Abstract »    Full Text »    PDF »
The Mitochondrial Toxin 3-Nitropropionic Acid Induces Striatal Neurodegeneration via a c-Jun N-Terminal Kinase/c-Jun Module.
M. Garcia, P. Vanhoutte, C. Pages, M.-J. Besson, E. Brouillet, and J. Caboche (2002)
J. Neurosci. 22, 2174-2184
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882