Heme oxygenase-1 posttranslational modifications in the brain of subjects with Alzheimer disease and mild cognitive impairment

Eugenio Barone, Fabio Di Domenico, Rukhsana Sultana, Raffaella Coccia, Cesare Mancuso, Marzia Perluigi, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

103 Scopus citations


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.

Original languageEnglish
Pages (from-to)2292-2301
Number of pages10
JournalFree Radical Biology and Medicine
Issue number11-12
StatePublished - Jun 1 2012

Bibliographical note

Funding Information:
This work was supported in part by an NIH Grant to D.A.B. ( AG-05119 ). This work also was supported by a grant PRIN 2009 of the Italian Ministry of Education, University and Research to C.M. We are grateful to the Neuropathology Core of the University of Kentucky Alzheimer's Disease Clinical Center for providing well characterized specimens for this research.


  • Alzheimer disease
  • Free radicals
  • Heme oxygenase
  • Mild cognitive impairment
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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