PARP-1 modulates amyloid beta peptide-induced neuronal damage

• Published in: PloS one 2013-09, Vol.8 (9), p.e72169
• Main Authors: Martire, Sara, Fuso, Andrea, Rotili, Dante, Tempera, Italo, Giordano, Cesare, De Zottis, Ivana, Muzi, Alessia, Vernole, Patrizia, Graziani, Grazia, Lococo, Emanuela, Faraldi, Martina, Maras, Bruno, Scarpa, Sigfrido, Mosca, Luciana, d'Erme, Maria
• Format: Article
• Language: English
• Subjects: Adenosine diphosphate; Alzheimer's disease; Amyloid beta-Peptides - toxicity; Animals; Apoptosis; Base Sequence; Bcl-2 protein; Brain research; Cancer; Cell Line; CHO Cells; Comet Assay; Cricetinae; Cricetulus; Damage; Deoxyribonucleic acid; DNA; DNA Damage; DNA Primers; Electrophoretic Mobility Shift Assay; Enzymes; Free radicals; Gene expression; Genetic engineering; Kinases; Medical research; Mice; Mice, Transgenic; Monosaccharides; Neuroblastoma; Neuroblastoma cells; Neurodegeneration; Neurons; Neurons - drug effects; Neurosciences; Neurotoxicity; NF-κB protein; Oxidative stress; p53 Protein; Peptide Fragments - toxicity; Peptides; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - physiology; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; Ribose; Rodents; Signal transduction; Transgenic mice; Tumor proteins; β-Amyloid
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0072169

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.