The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: It's time for reconciliation

Eugenio Barone, Fabio Di Domenico, Cesare Mancuso, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

110 Scopus citations

Abstract

Alzheimer disease (AD) is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. These clinical features are due in part to the increase of reactive oxygen and nitrogen species that mediate neurotoxic effects. The up-regulation of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system is one of the earlier events in the adaptive response to stress. HO-1/BVR-A reduces the intracellular levels of pro-oxidant heme and generates equimolar amounts of the free radical scavengers biliverdin-IX alpha (BV)/bilirubin-IX alpha (BR) as well as the pleiotropic gaseous neuromodulator carbon monoxide (CO) and ferrous iron. Two main and opposite hypotheses for a role of the HO-1/BVR-A system in AD propose that this system mediates neurotoxic and neuroprotective effects, respectively. This apparent controversy was mainly due to the fact that for over about 20. years HO-1 was the only player on which all the analyses were focused, excluding the other important and essential component of the entire system, BVR. Following studies from the Butterfield laboratory that reported alterations in BVR activity along with decreased phosphorylation and increased oxidative/nitrosative post-translational modifications in the brain of subjects with AD and amnestic mild cognitive impairment (MCI) subjects, a debate was opened on the real pathophysiological and clinical significance of BVR-A. In this paper we provide a review of the main discoveries about the HO/BVR system in AD and MCI, and propose a mechanism that reconciles these two hypotheses noted above of neurotoxic and the neuroprotective aspects of this important stress responsive system.

Original languageEnglish
Pages (from-to)144-159
Number of pages16
JournalNeurobiology of Disease
Volume62
DOIs
StatePublished - Feb 2014

Bibliographical note

Funding Information:
This work was supported in part by a NIH grant to DAB [ AG-05119 ] and Fondi Ateneo to CM.

Keywords

  • Aging
  • Alzheimer disease
  • Biliverdin reductase
  • Heme oxygenase
  • Mild cognitive impairment
  • Oxidative stress

ASJC Scopus subject areas

  • Neurology

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