Molecular Connections between DNA Replication and Cell Death in β-Amyloid-Treated Neurons
Filippo Caraci1,2, Annamaria Fidilio2, Rosa Santangelo1
1Department of Drug and Health Sciences, University of Catania, Catania, Italy.
Current Neuropharmacology
|April 6, 2023
Summary
In Alzheimer's disease, blocking the ATM-ATR/Claspin/Chk-1 pathway promotes neuronal DNA replication and apoptosis. Preserving Claspin on DNA replication forks prevents neuron death, suggesting its degradation triggers apoptosis.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Ectopic neuronal cell cycle re-entry is linked to neuronal death in Alzheimer's disease (AD).
- Beta-amyloid (Aβ) triggers neuronal cell cycle re-entry and DNA replication via DNA polymerase-β, leading to neurodegeneration.
- The precise molecular mechanisms connecting DNA replication to neuronal apoptosis in AD remain unclear.
Purpose of the Study:
- To investigate the role of the ATM-ATR/Claspin/Chk-1 checkpoint pathway in mediating the switch from neuronal DNA replication to apoptosis following Aβ exposure.
- To elucidate how DNA replication stress influences neuronal fate in an Alzheimer's disease model.
Main Methods:
- Cultured rat cortical neurons were treated with toxic Aβ oligomers.
- The effects of ATM/ATR kinase and Chk-1 inhibitors on DNA replication and apoptosis were assessed.
- Claspin localization at DNA replication forks and the impact of caspase inhibition and a Claspin-mimicking peptide on neuronal survival were examined.
Main Results:
- Inhibiting ATM/ATR or Chk-1 exacerbated Aβ-induced neuronal DNA replication and apoptosis.
- Claspin was detected at replication forks early after Aβ challenge but decreased as apoptosis ensued.
- Maintaining Claspin levels at replication forks via caspase inhibition or using a Claspin-mimicking peptide protected neurons from apoptosis by arresting them in S phase.
Conclusions:
- Claspin degradation may be a critical event precipitating neuronal apoptosis in Alzheimer's disease.
- The ATM-ATR/Claspin/Chk-1 pathway plays a crucial role in regulating neuronal response to DNA replication stress in AD.
- Targeting Claspin stability could offer a therapeutic strategy for preventing neurodegeneration in Alzheimer's disease.
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