Abstract
Amyloid beta (Abeta) is a main component of senile plaques in Alzheimer's disease and induces neuronal cell death. Reactive oxygen species (ROS), nitric oxide and endoplasmic reticulum (ER) stress have been implicated in Abeta-induced neurotoxicity. We have reported that apoptosis signal-regulating kinase 1 (ASK1) is required for ROS- and ER stress-induced JNK activation and apoptosis. Here we show the involvement of ASK1 in Abeta-induced neuronal cell death. Abeta activated ASK1 mainly through production of ROS but not through ER stress in cultured neuronal cells. Importantly, ASK1-/- neurons were defective in Abeta-induced JNK activation and cell death. These results indicate that ROS-mediated ASK1 activation is a key mechanism for Abeta-induced neurotoxicity, which plays a central role in Alzheimer's disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / etiology
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Amyloid beta-Peptides / pharmacology*
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Animals
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Cell Death / drug effects
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Endoplasmic Reticulum / enzymology
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Endoplasmic Reticulum / metabolism
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Enzyme Activation / drug effects
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JNK Mitogen-Activated Protein Kinases / metabolism
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MAP Kinase Kinase Kinase 5 / genetics
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MAP Kinase Kinase Kinase 5 / metabolism*
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neurons / cytology
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Neurons / drug effects*
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Neurons / metabolism
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Nitrogen Oxides / metabolism
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PC12 Cells
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Peptide Fragments / pharmacology
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Protein Serine-Threonine Kinases / metabolism
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Rats
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Reactive Oxygen Species / metabolism*
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eIF-2 Kinase / metabolism
Substances
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Amyloid beta-Peptides
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Membrane Proteins
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Nitrogen Oxides
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Peptide Fragments
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Reactive Oxygen Species
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amyloid beta-protein (1-42)
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Ern2 protein, rat
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PERK kinase
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Protein Serine-Threonine Kinases
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eIF-2 Kinase
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 5