Abstract
Alzheimer’s disease (AD) is the most common form of dementia, characterized by a decline in memory and cognitive function. Clinical manifestations of AD are closely associated with the formation of senile plaques and neurofibrillary tangles, neuronal loss and cognitive decline. Apoptosis signal regulating kinase 1 (ASK1) is a mediator of the MAPK pathway, which regulates various cellular responses such as apoptosis, cell survival, and differentiation. Accumulating evidence indicates that ASK1 plays a key role in the pathogenesis of neurodegenerative disorders such as Huntington’s disease and AD. Of particular interest, ASK1 is associated with many signaling pathways, which include endoplasmic reticulum (ER) stress-mediated apoptosis, Aβ-induced neurotoxicity, tau protein phosphorylation, and insulin signal transduction. Here, we review experimental evidence that links ASK1 signaling and AD pathogenesis and propose that ASK1 might be a new point of therapeutic intervention to prevent or treat AD.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by neuronal loss, aggregation of senile plaques derived from amyloid beta (Aβ) peptides, abnormal phosphorylation of tau protein and cognitive decline in the hippocampus or cortex [1,2]
AD is characterized by neuronal loss, Aβ accumulation, abnormal phosphorylation of tau protein, and cognitive decline in the hippocampus or cortex
Apoptosis signal-regulating kinase 1 (ASK1) is associated with insulin signal transduction, an important signaling component in cognitive decline
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by neuronal loss, aggregation of senile plaques derived from amyloid beta (Aβ) peptides, abnormal phosphorylation of tau protein and cognitive decline in the hippocampus or cortex [1,2]. ASK1 is activated in response to various stresses including tumor necrosis factor (TNF), endoplasmic reticulum (ER) stress, and H2O2 [4,5,8,9,10]. Aβ leading to AD pathology [11] can activate ASK1 that is required for ROS and ER stress-induced. Insulin like growth factor-1 receptor (IGF-IR) signaling suppresses the ASK1 mediated activation of JNK/p38 pathway. Insulin-like growth factor-1 (IGF-I) can suppress apoptosis, interfere downstream of tumor necrosis factor receptor (TNF-R) activation [16] and block the ASK1 mediated JNK activation by Aβ [17]. ASK1 is involved in insulin signal transduction through TNF-α-induced JNK signaling [25]. ASK1 is associated with various mechanisms, which include cell death, Aβ neurotoxicity, abnormal phosphorylation of tau protein and impaired insulin signal transduction. ASK1 is involved in mechanisms related to AD pathology
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