title: Heme oxygenase-1 posttranslational modifications in the brain of subjects with Alzheimer disease and mild cognitive impairment.
abstract: Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Oxidative and nitrosative stress plays a principal role in the pathogenesis of AD. The induction of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system in the brain represents one of the earliest mechanisms activated by cells to counteract the noxious effects of increased reactive oxygen species and reactive nitrogen species. Although initially proposed as a neuroprotective system in AD brain, the HO-1/BVR-A pathophysiological features are under debate. We previously reported alterations in BVR activity along with decreased phosphorylation and increased oxidative/nitrosative posttranslational modifications in the brain of subjects with AD and those with mild cognitive impairment (MCI). Furthermore, other groups proposed the observed increase in HO-1 in AD brain as a possible neurotoxic mechanism. Here we provide new insights about HO-1 in the brain of subjects with AD and MCI, the latter condition being the transitional phase between normal aging and early AD. HO-1 protein levels were significantly increased in the hippocampus of AD subjects, whereas HO-2 protein levels were significantly decreased in both AD and MCI hippocampi. In addition, significant increases in Ser-residue phosphorylation together with increased oxidative posttranslational modifications were found in the hippocampus of AD subjects. Interestingly, despite the lack of oxidative stress-induced AD neuropathology in cerebellum, HO-1 demonstrated increased Ser-residue phosphorylation and oxidative posttranslational modifications in this brain area, suggesting HO-1 as a target of oxidative damage even in the cerebellum. The significance of these findings is profound and opens new avenues into the comprehension of the role of HO-1 in the pathogenesis of AD.
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: Rukhsana
authors.initials: R
authors.lastname: Sultana
authors.forename: Raffaella
authors.initials: R
authors.lastname: Coccia
authors.forename: Cesare
authors.initials: C
authors.lastname: Mancuso
authors.forename: Marzia
authors.initials: M
authors.lastname: Perluigi
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D060825:Cognitive Dysfunction / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D018384:Oxidative Stress; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D051547:Heme Oxygenase-1