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The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: It's time for reconciliation
Open accessAbstract
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 20years 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.
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“It also suggests that atorvastatin, although not a direct antioxidant and not able to cross the BBB, leads to antioxidant-like effects in brain100.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [100]
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“BVR-A, in addition to being a reductase, is a kinase that can phosphorylate insulin receptor substrate-1100.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [100]
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“Both HO-1 and BVR-A are oxidatively damaged in aMCI and AD brain100.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [100]
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“BVR-A is nitrosatively modified and dysfunctional in AD and MCI brain100, and its impairment promotes insulin resistance101.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [100]
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“Recently, intranasal treatment of a 3 X Tg mice model of AD with insulin showed a significant reduction of brain nitrosative stress, tau phosphorylation, and Aβ oligomers coupled to improved cognition, and these effects were dependent on the activity of biliverdin reductase-A (BVR-A)99,100.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [100]
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Metadata
- Authors
- Barone, E., Di Domenico, F., Mancuso, C., & Butterfield, D. A.
- Affiliations
- University of Kentucky (US)
- Università Cattolica del Sacro Cuore (IT)
- Corresponding author
- Butterfield, D. Allan
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 62
- Pages
- 144-159
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC3877707
- OpenAlex
- W2082990108
- Cited by
- 127
- References
- 227
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 10 · 2022: 8 · 2021: 12 · 2020: 15 · 2019: 12 · 2018: 10 · 2017: 8 · 2016: 8 · 2015: 18 · 2014: 11
- FWCI
- 1.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- NIH (AG-05119)
- Fondi Ateneo
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, heme oxygenase-1, biliverdin reductase A, biliverdin, bilirubin, carbon monoxide, ferrous iron, oxidative stress, nitrosative stress, neuroprotection, neurotoxicity, amnestic mild cognitive impairment, post-translational modification, stress response
- MeSH terms
- Alzheimer Disease, Animals, Brain, Heme Oxygenase (Decyclizing), Humans, Models, Neurological, Oxidative Stress, Oxidoreductases Acting on CH-CH Group Donors
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