PARP-1 modulates amyloid beta peptide-induced neuronal damage

PLoS One. 2013 Sep 24;8(9):e72169. doi: 10.1371/journal.pone.0072169. eCollection 2013.

Abstract

Amyloid beta peptide (Aβ) causes neurodegeneration by several mechanisms including oxidative stress, which is known to induce DNA damage with the consequent activation of poly (ADP-ribose) polymerase (PARP-1). To elucidate the role of PARP-1 in the neurodegenerative process, SH-SY5Y neuroblastoma cells were treated with Aβ25-35 fragment in the presence or absence of MC2050, a new PARP-1 inhibitor. Aβ25-35 induces an enhancement of PARP activity which is prevented by cell pre-treatment with MC2050. These data were confirmed by measuring PARP-1 activity in CHO cells transfected with amylod precursor protein and in vivo in brains specimens of TgCRND8 transgenic mice overproducing the amyloid peptide. Following Aβ25-35 exposure a significant increase in intracellular ROS was observed. These data were supported by the finding that Aβ25-35 induces DNA damage which in turn activates PARP-1. Challenge with Aβ25-35 is also able to activate NF-kB via PARP-1, as demonstrated by NF-kB impairment upon MC2050 treatment. Moreover, Aβ25-35 via PARP-1 induces a significant increase in the p53 protein level and a parallel decrease in the anti-apoptotic Bcl-2 protein. These overall data support the hypothesis of PARP-1 involvment in cellular responses induced by Aβ and hence a possible rationale for the implication of PARP-1 in neurodegeneration is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Base Sequence
  • CHO Cells
  • Cell Line
  • Comet Assay
  • Cricetinae
  • Cricetulus
  • DNA Damage
  • DNA Primers
  • Electrophoretic Mobility Shift Assay
  • Mice
  • Mice, Transgenic
  • Neurons / drug effects*
  • Peptide Fragments / toxicity*
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / physiology*
  • Reactive Oxygen Species / metabolism

Substances

  • Amyloid beta-Peptides
  • DNA Primers
  • Peptide Fragments
  • Reactive Oxygen Species
  • amyloid beta-protein (25-35)
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases

Grant support

This work was supported by funds from MIUR and from Istituto Pasteur, Fondazione Cenci Bolognetti, Roma, Italy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.