Amyloid beta induces neuronal cell death through ROS-mediated ASK1 activation.
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.
Kadowaki
H
H
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Nishitoh
H
H
Urano
F
F
Sadamitsu
C
C
Matsuzawa
A
A
Takeda
K
K
Masutani
H
H
Yodoi
J
J
Urano
Y
Y
Nagano
T
T
Ichijo
H
H
D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism
D016229:Amyloid beta-Peptides; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D008565:Membrane Proteins; D009589:Nitrogen Oxides; D010446:Peptide Fragments; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D019892:eIF-2 Kinase; C075222:amyloid beta-protein (1-42); C486557:Ern2 protein, rat