In:
Current Neuropharmacology, Bentham Science Publishers Ltd., Vol. 21, No. 9 ( 2023-09), p. 2006-2018
Abstract:
Ectopic cell cycle reactivation in neurons is associated with neuronal death in
Alzheimer’s disease. In cultured rodent neurons, synthetic β-amyloid (Aβ) reproduces the neuronal cell cycle re-entry observed in the Alzheimer’s brain, and blockade of the cycle prevents Aβ-induced
neurodegeneration. DNA polymerase-β, whose expression is induced by Aβ, is responsible for the DNA replication process that ultimately leads to neuronal death, but the molecular mechanism(s) linking
DNA replication to neuronal apoptosis are presently unknown. Aim: To explore the role of a conserved checkpoint pathway started by DNA replication stress, namely
the ATM-ATR/Claspin/Chk-1 pathway, in switching the neuronal response from DNA replication to apoptosis. Methods: Experiments were carried out in cultured rat cortical neurons challenged with toxic oligomers
of Aβ protein. Results: Small inhibitory molecules of ATM/ATR kinase or Chk-1 amplified Aβ-induced neuronal
DNA replication and apoptosis, as they were permissive to the DNA polymerase-β activity triggered by Aβ oligomers. Claspin, i.e., the adaptor protein between ATM/ATR kinase and the downstream
Chk-1, was present on DNA replication forks of neurons early after Aβ challenge, and decreased at times coinciding with neuronal apoptosis. The caspase-3/7 inhibitor I maintained overtime the amount
of Claspin loaded on DNA replication forks and, concomitantly, reduced neuronal apoptosis by holding neurons in the S phase. Moreover, a short phosphopeptide mimicking the Chk-1-binding motif of
Claspin was able to prevent Aβ-challenged neurons from entering apoptosis. Conclusion: We speculate that, in the Alzheimer’s brain, Claspin degradation by intervening factors
may precipitate the death of neurons engaged into DNA replication.
Type of Medium:
Online Resource
ISSN:
1570-159X
DOI:
10.2174/1570159X21666230404121903
Language:
English
Publisher:
Bentham Science Publishers Ltd.
Publication Date:
2023
detail.hit.zdb_id:
2119376-9
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