title: Alzheimer's disease-associated neurotoxic peptide amyloid-β impairs base excision repair in human neuroblastoma cells.
abstract: Alzheimer's disease (AD) is the leading cause of dementia in developed countries. It is characterized by two major pathological hallmarks, one of which is the extracellular aggregation of the neurotoxic peptide amyloid-β (Aβ), which is known to generate oxidative stress. In this study, we showed that the presence of Aβ in a neuroblastoma cell line led to an increase in both nuclear and mitochondrial DNA damage. Unexpectedly, a concomitant decrease in basal level of base excision repair, a major route for repairing oxidative DNA damage, was observed at the levels of both gene expression and protein activity. Moreover, the addition of copper sulfate or hydrogen peroxide, used to mimic the oxidative stress observed in AD-affected brains, potentiates Aβ-mediated perturbation of DNA damage/repair systems in the "Aβ cell line". Taken together, these findings indicate that Aβ could act as double-edged sword by both increasing oxidative nuclear/mitochondrial damage and preventing its repair. The synergistic effects of increased ROS production, accumulated DNA damage and impaired DNA repair could participate in, and partly explain, the massive loss of neurons observed in Alzheimer's disease since both oxidative stress and DNA damage can trigger apoptosis.
authors.affiliation: Nucleic Acids Lesions Laboratory, SCIB/INAC, CEA, Joseph Fourier University-Grenoble 1,  17 rue des Martyrs, 38054 Grenoble Cedex 9, France. walid.rachidi@cea.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Forestier
authors.forename: Thierry
authors.initials: T
authors.lastname: Douki
authors.forename: Sylvie
authors.initials: S
authors.lastname: Sauvaigo
authors.forename: Viviana
authors.initials: V
authors.lastname: De Rosa
authors.forename: Christine
authors.initials: C
authors.lastname: Demeilliers
authors.forename: Walid
authors.initials: W
authors.lastname: Rachidi
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D004272:DNA, Mitochondrial; D016877:Oxidants; D010446:Peptide Fragments; D006151:Guanosine; C046215:8-hydroxyguanosine