DNA polymerase-β is expressed early in neurons of Alzheimer's disease brain and is loaded into DNA replication forks in neurons challenged with β-amyloid

Agata Copani, J. J M Hoozemans, Filippo Caraci, Marco Calafiore, Elise S. Van Haastert, Robert Veerhuis, A. J M Rozemuller, Eleonora Aronica, Maria Angela Sortino, Ferdinando Nicoletti

Research output: Contribution to journalArticle

Abstract

Cultured neurons exposed to synthetic β-amyloid (Aβ) fragments reenter the cell cycle and initiate a pathway of DNA replication that involves the repair enzyme DNA polymerase-β (DNA pol-β) before undergoing apoptotic death. In this study, by performing coimmunoprecipitation experiments on cross-linked nucleoprotein fragments from Aβ-treated neurons, we demonstrate that DNA pol-β coimmunoprecipitates with cell division cycle 45 (Cdc45) and with DNA primase in short nucleoprotein fragments. This indicates that DNA pol-β is loaded into neuronal DNA replication forks after Aβ treatment. In response to Aβ the canonical DNA-synthesizing enzyme DNA pol-δ also was loaded into neuronal replication forks, but at later times than DNA pol-β. Methoxyamine, an inhibitor of the apurinic/apyrimidinic endonuclease that allows for the recruitment of DNA pol-β during the process of base excision repair (BER), failed to affect coimmunoprecipitation between DNA pol-β and Cdc45, indicating that DNA pol-β loading to the replication forks is independent of DNA breaks. However, methoxyamine reduced DNA replication and ensuing apoptosis in neurons exposed to Aβ, suggesting that an efficient BER process allows DNA replication to proceed up to the threshold for death. These data demonstrate that DNA pol-β is an essential component of the DNA replication machinery in Aβ-treated neurons and additionally support the hypothesis of a close association of cell cycle events with neuronal death in Alzheimer's disease (AD). Accordingly, by investigating the neuronal expression of DNA pol-β, along with phosphorylated retinoblastoma protein and neurofibrillary changes in AD brain, we show an early involvement of DNA pol-β in the pathogenesis of AD.

Original languageEnglish
Pages (from-to)10949-10957
Number of pages9
JournalJournal of Neuroscience
Volume26
Issue number43
DOIs
Publication statusPublished - Oct 25 2006

Keywords

  • β-amyloid
  • APE-1/Ref-1
  • DNA polymerase-β
  • DNA repair
  • DNA replication
  • Methoxyamine

ASJC Scopus subject areas

  • Neuroscience(all)

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