title: Multiple mechanisms of iron-induced amyloid beta-peptide accumulation in SHSY5Y cells: protective action of negletein.
abstract: The increased accumulation of iron in the brain in Alzheimer's disease (AD) is well documented, and excess iron is strongly implicated in the pathogenesis of the disease. The adverse effects of accumulated iron in AD brain may include the oxidative stress, altered amyloid beta-metabolism and the augmented toxicity of metal-bound amyloid beta 42. In this study, we have shown that exogenously added iron in the form of ferric ammonium citrate (FAC) leads to considerable accumulation of amyloid precursor protein (APP) without a corresponding change in the concerned gene expression in cultured SHSY5Y cells during exposure up to 48 h. This phenomenon is also associated with increased β-secretase activity and augmented release of amyloid beta 42 in the medium. Further, the increase in β-secretase activity, in SHSY5Y cells, upon exposure to iron apparently involves reactive oxygen species (ROS) and NF-κB activation. The synthetic flavone negletein (5,6-dihydroxy-7-methoxyflavone), which is a known chelator for iron, can significantly prevent the effects of FAC on APP metabolism in SHSY5Y cells. Further, this compound inhibits the iron-dependent formation of ROS and also blocks the iron-induced oligomerization of amyloid beta 42 in vitro. In concentrations used in this study, negletein alone appears to have only marginal toxic effects on cell viability, but, on the other hand, the drug is capable of ameliorating the iron-induced loss of cell viability considerably. Our results provide the initial evidence of potential therapeutic effects of negletein, which should be explored in suitable animal models of AD.
authors.affiliation: Department of Biochemistry, Institute of Postgraduate Medical Education and Research, 244, AJC Bose Road, Kolkata, 700020, India.
authors.forename: Priyanjalee
authors.initials: P
authors.lastname: Banerjee
authors.forename: Arghyadip
authors.initials: A
authors.lastname: Sahoo
authors.forename: Shruti
authors.initials: S
authors.lastname: Anand
authors.forename: Anirban
authors.initials: A
authors.lastname: Ganguly
authors.forename: Giuliana
authors.initials: G
authors.lastname: Righi
authors.forename: Paolo
authors.initials: P
authors.lastname: Bovicelli
authors.forename: Luciano
authors.initials: L
authors.lastname: Saso
authors.forename: Sasanka
authors.initials: S
authors.lastname: Chakrabarti
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001205:Ascorbic Acid / Q000494:pharmacology; D045744:Cell Line, Tumor; D005290:Ferric Compounds / Q000494:pharmacology*; D047309:Flavones / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology* / Q000633:toxicity; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D058105:Polymerization; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D005290:Ferric Compounds; D047309:Flavones; D007502:Iron Chelating Agents; D016328:NF-kappa B; D010446:Peptide Fragments; D000644:Quaternary Ammonium Compounds; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); C507557:negletein; D017665:Hydroxyl Radical; D007501:Iron; D053829:Amyloid Precursor Protein Secretases; D001205:Ascorbic Acid; C013531:ferric ammonium citrate