Heme oxygenase-1 and neurodegeneration: expanding frontiers of engagement
Open accessAbstract
The heme oxygenases (HOs), responsible for the degradation of heme to biliverdin/bilirubin, free iron and CO, have been heavily implicated in mammalian CNS aging and disease. In normal brain, the expression of HO-2 is constitutive, abundant and fairly ubiquitous, whereas HO-1 mRNA and protein are confined to small populations of scattered neurons and neuroglia. In contradistinction to HO-2, the ho-1 gene (Hmox1) is exquisitely sensitive to induction by a wide range of pro-oxidant and other stressors. In Alzheimer disease and mild cognitive impairment, immunoreactive HO-1 protein is over-expressed in neurons and astrocytes of the cerebral cortex and hippocampus relative to age-matched, cognitively intact controls and co-localizes to senile plaques, neurofibrillary tangles, and corpora amylacea. In Parkinson disease, HO-1 is markedly over-expressed in astrocytes of the substantia nigra and decorates Lewy bodies in affected dopaminergic neurons. HMOX1 is also up-regulated in glial cells surrounding human cerebral infarcts, hemorrhages and contusions, within multiple sclerosis plaques, and in other degenerative and inflammatory human CNS disorders. Heme-derived free ferrous iron, CO, and biliverdin/bilirubin are biologically active substances that have been shown to either ameliorate or exacerbate neural injury contingent upon specific disease models employed, the intensity and duration of HO-1 expression and the nature of the prevailing redox microenvironment. In 'stressed' astroglia, HO-1 hyperactivity promotes mitochondrial sequestration of non-transferrin iron and macroautophagy and may thereby contribute to the pathological iron deposition and bioenergetic failure amply documented in Alzheimer disease, Parkinson disease and other aging-related neurodegenerative disorders. Glial HO-1 expression may also impact cell survival and neuroplasticity in these conditions by modulating brain sterol metabolism and proteosomal degradation of neurotoxic protein aggregates.
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Up-regulation of HO-1 in glia might contribute to neurodegeneration; as brains age, prolonged action of HO-1 in astrocytes is likely to be involved in iron sequestration, intracellular oxidative stress, and mitochondrial insufficiency.
“Although haem oxygenase 1 (HO-1) is considered to be cytoprotective, up-regulation of this enzyme in glia might contribute to neurodegeneration: as brains age, the prolonged action of HO-1 in astrocytes is likely to be involved in iron sequestration, intracellular oxidative stress, and mitochondrial insufficiency.56”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [56]
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Stress protein expression in the Alzheimer-diseased choroid plexus
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Self-citationIron content correlates with peroxidase activity in cysteamine-induced astroglial organelles.
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- Authors
- Schipper, H. M., Song, W., Zukor, H., Hascalovici, J. R., & Zeligman, D.
- Affiliations
- Jewish General Hospital (CA)
- Corresponding author
- Schipper, Hyman M.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2009-06-25
- Volume
- 110
- Issue
- 2
- Pages
- 469-485
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2001357290
- Cited by
- 298
- References
- 184
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 21 · 2023: 13 · 2022: 18 · 2021: 26 · 2020: 19 · 2019: 16 · 2018: 13 · 2017: 11 · 2016: 15 · 2015: 24 · 2014: 21 · 2013: 23 · 2012: 19
- FWCI
- 1.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
- Keywords
- heme oxygenase-1, heme oxygenase-2, neurodegeneration, Alzheimer's disease, Parkinson's disease, mild cognitive impairment, astrocytes, Lewy bodies, amyloid plaques, neurofibrillary tangles, cerebral infarction, multiple sclerosis, iron metabolism, bilirubin, carbon monoxide, macroautophagy, neuroplasticity, protein aggregation
- MeSH terms
- Animals, Humans, Nerve Degeneration, Signal Transduction, Neurodegenerative Diseases, Heme Oxygenase-1
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