Amyloid β induces neuronal cell death through ROS-mediated ASK1 activation

Amyloid β (A β ) 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 A β -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 A β -induced neuronal cell death. A β activated ASK1 mainly through production of ROS but not through ER stress in cultured neuronal cells. Importantly, ASK1 −/− neurons were defective in A β -induced JNK activation and cell death. These results indicate that ROS-mediated ASK1 activation is a key mechanism for A β -induced neurotoxicity, which plays a central role in Alzheimer's disease.