Neurotoxic Mechanisms Caused by the Alzheimer's Disease-linked Swedish Amyloid Precursor Protein Mutation

Autosomal dominant forms of familial Alzheimer's disease (FAD) are caused by mutations of the amyloid precursor protein (APP) gene and by mutations of the genes encoding for presenilin 1 or presenilin 2. Simultaneously, evidence is provided that increased oxidative stress might play a crucial role in the rapid progression of the Swedish FAD. Here we investigated the effect of the Swedish double mutation (K670M/N671L) in the β-amyloid precursor protein on oxidative stress-induced cell death mechanisms in PC12 cells. Western blot analysis and cleavage studies of caspase substrates revealed an elevated activity of the executor caspase 3 after treatment with hydrogen peroxide in cells containing the Swedish APP mutation. This elevated activity is the result of the enhanced activation of both intrinsic and extrinsic apoptosis pathways, including activation of caspase 2 and caspase 8. Furthermore, we observed an enhanced activation of JNK pathway and an attenuation of apoptosis by SP600125, a JNK inhibitor, through protection of mitochondrial dysfunction and reduction of caspase 9 activity. Our findings provide evidence that the massive neurodegeneration in early age of FAD patients could be a result of an increased vulnerability of neurons through activation of different apoptotic pathways as a consequence of elevated levels of oxidative stress.

[1]  Hongqiao Li,et al.  Mammalian APH-1 Interacts with Presenilin and Nicastrin and Is Required for Intramembrane Proteolysis of Amyloid-β Precursor Protein and Notch* , 2002, The Journal of Biological Chemistry.

[2]  J. Lee,et al.  Amyloid-β Induces Smac Release via AP-1/Bim Activation in Cerebral Endothelial Cells , 2002, The Journal of Neuroscience.

[3]  H. Ichijo,et al.  Phosphorylation and Inactivation of Myeloid Cell Leukemia 1 by JNK in Response to Oxidative Stress* , 2002, The Journal of Biological Chemistry.

[4]  T. Arendt,et al.  Aberrant expression of NOS isoforms in Alzheimer’s disease is structurally related to nitrotyrosine formation , 2002, Brain Research.

[5]  Ralf Langen,et al.  Structural and Dynamic Features of Alzheimer's Aβ Peptide in Amyloid Fibrils Studied by Site-directed Spin Labeling* , 2002, The Journal of Biological Chemistry.

[6]  D. Selkoe.  Alzheimer's Disease Is a Synaptic Failure , 2002, Science.

[7]  Harald Steiner,et al.  PEN-2 Is an Integral Component of the γ-Secretase Complex Required for Coordinated Expression of Presenilin and Nicastrin* , 2002, The Journal of Biological Chemistry.

[8]  David S. Park,et al.  Interaction of the c-Jun/JNK Pathway and Cyclin-dependent Kinases in Death of Embryonic Cortical Neurons Evoked by DNA Damage* , 2002, The Journal of Biological Chemistry.

[9]  Ximena Opitz-Araya,et al.  Requirement for Caspase-2 in Stress-Induced Apoptosis Before Mitochondrial Permeabilization , 2002, Science.

[10]  Sten Orrenius,et al.  Caspase-2 Acts Upstream of Mitochondria to Promote Cytochromec Release during Etoposide-induced Apoptosis* , 2002, The Journal of Biological Chemistry.

[11]  P. S. St George-Hyslop,et al.  Mature Glycosylation and Trafficking of Nicastrin Modulate Its Binding to Presenilins* 210 , 2002, The Journal of Biological Chemistry.

[12]  G. Perry,et al.  Oxidative Stress Increases Expression and Activity of BACE in NT2 Neurons , 2002, Neurobiology of Disease.

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

[14]  G. Gibson.  Interactions of oxidative stress with cellular calcium dynamics and glucose metabolism in Alzheimer's disease. , 2002, Free radical biology & medicine.

[15]  D. Allsop,et al.  Formation of hydrogen peroxide and hydroxyl radicals from Aβ and α-synuclein as a possible mechanism of cell death in Alzheimer’s disease and Parkinson’s disease. , 2002 .

[16]  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.

[17]  C. Schneider,et al.  Caspase-2 Can Trigger Cytochrome c Release and Apoptosis from the Nucleus* , 2002, The Journal of Biological Chemistry.

[18]  S. Srinivasula,et al.  Caspase-2 Induces Apoptosis by Releasing Proapoptotic Proteins from Mitochondria* , 2002, The Journal of Biological Chemistry.

[19]  R. Gottlieb,et al.  Analyzing mitochondrial changes during apoptosis. , 2002, Methods.

[20]  P. Kang,et al.  Direct Activation of Mitochondrial Apoptosis Machinery by c-Jun N-terminal Kinase in Adult Cardiac Myocytes* , 2002, The Journal of Biological Chemistry.

[21]  M. Yoshizumi,et al.  Hydrogen Peroxide Stimulates c-Src-mediated Big Mitogen-activated Protein Kinase 1 (BMK1) and the MEF2C Signaling Pathway in PC12 Cells , 2002, The Journal of Biological Chemistry.

[22]  H. Huttunen,et al.  Receptor for Advanced Glycation End Products Plays a More Important Role in Cellular Survival than in Neurite Outgrowth during Retinoic Acid-induced Differentiation of Neuroblastoma Cells* , 2002, The Journal of Biological Chemistry.

[23]  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.

[24]  L. Goldstein,et al.  Kinesin-mediated axonal transport of a membrane compartment containing β-secretase and presenilin-1 requires APP , 2001, Nature.

[25]  David W. Anderson,et al.  SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[26]  N. Bogdanovic,et al.  The Swedish APP670/671 Alzheimer’s Disease Mutation: The First Evidence for Strikingly Increased Oxidative Injury in the Temporal Inferior Cortex , 2001, Dementia and Geriatric Cognitive Disorders.

[27]  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.

[28]  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.

[29]  L. Greene,et al.  Death in the Balance: Alternative Participation of the Caspase-2 and -9 Pathways in Neuronal Death Induced by Nerve Growth Factor Deprivation , 2001, The Journal of Neuroscience.

[30]  Oliver Wirths,et al.  Intraneuronal Aβ accumulation precedes plaque formation in β-amyloid precursor protein and presenilin-1 double-transgenic mice , 2001, Neuroscience Letters.

[31]  S. Turner,et al.  Early-onset Amyloid Deposition and Cognitive Deficits in Transgenic Mice Expressing a Double Mutant Form of Amyloid Precursor Protein 695* , 2001, The Journal of Biological Chemistry.

[32]  C. Haass,et al.  Elevated vulnerability to oxidative stress‐induced cell death and activation of caspase‐3 by the Swedish amyloid precursor protein mutation , 2001, Journal of neuroscience research.

[33]  C. Luckhaus,et al.  Alzheimer's Disease-like Alterations in Peripheral Cells from Presenilin-1 Transgenic Mice , 2001, Neurobiology of Disease.

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

[35]  J. Blenis,et al.  Cargo of Kinesin Identified as Jip Scaffolding Proteins and Associated Signaling Molecules , 2001, The Journal of cell biology.

[36]  S. B. Bratton,et al.  Recruitment, activation and retention of caspases‐9 and ‐3 by Apaf‐1 apoptosome and associated XIAP complexes , 2001, The EMBO journal.

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

[38]  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.

[39]  Junying Yuan,et al.  Apoptosis in the nervous system , 2000, Nature.

[40]  S. Leutner,et al.  Reduced antioxidant enzyme activity in brains of mice transgenic for human presenilin-1 with single or multiple mutations , 2000, Neuroscience Letters.

[41]  N. Thornberry,et al.  Caspase-2 Is Localized at the Golgi Complex and Cleaves Golgin-160 during Apoptosis , 2000, The Journal of cell biology.

[42]  S. Rabacchi,et al.  Caspase-2 Mediates Neuronal Cell Death Induced by β-Amyloid , 2000, The Journal of Neuroscience.

[43]  Junying Yuan,et al.  Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β , 2000, Nature.

[44]  Alfredo G. Tomasselli,et al.  Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity , 1999, Nature.

[45]  J. Treanor,et al.  Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. , 1999, Science.

[46]  C. Cotman,et al.  Neuronal Apoptosis Induced by β-Amyloid Is Mediated by Caspase-8 , 1999, Neurobiology of Disease.

[47]  C. Bergeron,et al.  Caspase-6 Role in Apoptosis of Human Neurons, Amyloidogenesis, and Alzheimer’s Disease* , 1999, The Journal of Biological Chemistry.

[48]  M. Tabaton,et al.  Alternative, Non-secretase Processing of Alzheimer’s β-Amyloid Precursor Protein during Apoptosis by Caspase-6 and -8* , 1999, The Journal of Biological Chemistry.

[49]  Sten Orrenius,et al.  Caspases: their intracellular localization and translocation during apoptosis , 1999, Cell Death and Differentiation.

[50]  David Smith,et al.  Involvement of Caspases in Proteolytic Cleavage of Alzheimer’s Amyloid-β Precursor Protein and Amyloidogenic Aβ Peptide Formation , 1999, Cell.

[51]  K Paliga,et al.  Proteolytic Processing of the Alzheimer’s Disease Amyloid Precursor Protein within Its Cytoplasmic Domain by Caspase-like Proteases* , 1999, The Journal of Biological Chemistry.

[52]  P. Kloetzel,et al.  Expression of Alzheimer’s Disease-associated Presenilin-1 Is Controlled by Proteolytic Degradation and Complex Formation* , 1998, The Journal of Biological Chemistry.

[53]  C. Cotman,et al.  Apoptosis Decision Cascades and Neuronal Degeneration in Alzheimer’s Disease , 1998, Neurobiology of Aging.

[54]  D. Selkoe,et al.  The Proteolytic Fragments of the Alzheimer’s Disease-associated Presenilin-1 Form Heterodimers and Occur as a 100–150-kDa Molecular Mass Complex* , 1998, The Journal of Biological Chemistry.

[55]  M. Muda,et al.  Bcl-2 Undergoes Phosphorylation by c-Jun N-terminal Kinase/Stress-activated Protein Kinases in the Presence of the Constitutively Active GTP-binding Protein Rac1* , 1997, The Journal of Biological Chemistry.

[56]  M. Mattson.  Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. , 1997, Physiological reviews.

[57]  C. Masters,et al.  Distinct sites of intracellular production for Alzheimer's disease Aβ40/42 amyloid peptides , 1997, Nature Medicine.

[58]  M. Mattson,et al.  Alzheimer’s Presenilin Mutation Sensitizes Neural Cells to Apoptosis Induced by Trophic Factor Withdrawal and Amyloid β-Peptide: Involvement of Calcium and Oxyradicals , 1997, The Journal of Neuroscience.

[59]  W. Horton,et al.  Expression of mutant amyloid precursor proteins induces apoptosis in PC12 cells , 1997, Journal of neuroscience research.

[60]  D. Selkoe,et al.  Amyloid β-Protein and the Genetics of Alzheimer's Disease* , 1996, The Journal of Biological Chemistry.

[61]  R. Tanzi,et al.  REVIEWThe Gene Defects Responsible for Familial Alzheimer's Disease , 1996, Neurobiology of Disease.

[62]  D. Selkoe,et al.  The Swedish mutation causes early-onset Alzheimer's disease by β-secretase cleavage within the secretory pathway , 1995, Nature Medicine.

[63]  P. W. Mesner,et al.  A timetable of events during programmed cell death induced by trophic factor withdrawal from neuronal PC12 cells , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[64]  L. Zon,et al.  Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun , 1994, Nature.

[65]  D. Selkoe,et al.  Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid beta-protein precursor. , 1994, The Journal of biological chemistry.

[66]  S. Younkin,et al.  An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. , 1994, Science.

[67]  M. Mattson,et al.  A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[68]  C. Cotman,et al.  Apoptosis is induced by beta-amyloid in cultured central nervous system neurons. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[69]  S. Younkin,et al.  Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. , 1993, Science.

[70]  D. Selkoe,et al.  Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production , 1992, Nature.

[71]  M. Pericak-Vance,et al.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease , 1991, Nature.

[72]  C. Cotman,et al.  The influence of the carboxyl terminus of the Alzheimer Aβ peptide on its conformation, aggregation, and neurotoxic properties , 2002, NeuroMolecular Medicine.

[73]  Raymond Scott Turner,et al.  Animal Model Stable -Secretase Activity and Presynaptic Cholinergic Markers During Progressive Central Nervous System Amyloidogenesis in Tg2576 Mice , 2002 .

[74]  S H Kaufmann,et al.  Mammalian caspases: structure, activation, substrates, and functions during apoptosis. , 1999, Annual review of biochemistry.

[75]  T. Hartmann,et al.  Intracellular biology of Alzheimer’s disease amyloid beta peptide , 1999, European Archives of Psychiatry and Clinical Neuroscience.

[76]  C. Bieberich,et al.  The Alzheimer's Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice , 1995, Nature Genetics.