title: Oxidative and nitrosative modifications of biliverdin reductase-A in the brain of subjects with Alzheimer's disease and amnestic mild cognitive impairment.
abstract: Biliverdin reductase-A (BVR-A) is a pleiotropic enzyme and plays pivotal role in the antioxidant defense against free radicals as well as in cell homeostasis. Together with heme oxygenase, BVR-A forms a powerful system involved in the cell stress response during neurodegenerative disorders including Alzheimer's disease (AD), whereas due to the serine/threonine/tyrosine kinase activity the enzyme regulates glucose metabolism and cell proliferation. In this paper, we report results that demonstrate BVR-A undergoes post-translational oxidative and nitrosative modifications in the hippocampus, but not cerebellum, of subjects with AD and amnestic mild cognitive impairment (MCI). A significant increase of nitrated BVR-A was demonstrated only in AD and MCI hippocampi, whereas no significant modifications were found in cerebellar tissue. In addition, a significant reduction in protein carbonyl-derivatives of BVR-A was found in both AD and MCI hippocampi (15% and 18%, respectively). Biliverdin reductase-bound 4-hydroxynonenals were not modified in hippocampi and cerebella from AD and MCI subjects. These results supported the hypothesis of a prevalence of nitrosative stress-induced modifications on BVR-A structure, and this evidence was confirmed by a significant upregulation of inducible nitric oxide synthase in hippocampal tissue of subjects with AD and MCI that was not present in cerebellum. In conclusion, nitrosative stress-induced modifications on hippocampal BVR-A are an early event in the pathogenesis of AD since they appear also in MCI subjects and could contribute to the antioxidant and metabolic derangement characteristic of these neurodegenerative disorders.
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Barone
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Domenico
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cenini
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Sultana
authors.forename: Raffaella
authors.initials: R
authors.lastname: Coccia
authors.forename: Paolo
authors.initials: P
authors.lastname: Preziosi
authors.forename: Marzia
authors.initials: M
authors.lastname: Perluigi
authors.forename: Cesare
authors.initials: C
authors.lastname: Mancuso
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000447:Aldehydes / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism*; D050050:Protein Carbonylation / Q000502:physiology; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000447:Aldehydes; D026361:Reactive Nitrogen Species; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D006419:Heme Oxygenase (Decyclizing); D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; C027576:4-hydroxy-2-nonenal