Heme oxygenase‐1 and neurodegeneration: expanding frontiers of engagement

Abstract

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.

Metabolic cycles in a circannual hibernator

“…Only metabolites with ANOVA q Ͻ 0.05 are shown. and all three are involved in redox regulation (20,35). The changing levels of these molecules, particularly their rapid depletion at rewarming, are consistent with their playing a central role in ameliorating the potential damage inflicted by oxidative reperfusion upon arousal.…”

“…One of these was a group of three compounds that accumulated during torpor but rapidly diminished early in the arousal process, while the animals were still at low T b . Biliverdin and bilirubin are heme catabolites, and all three compounds have been implicated in redox regulation (35), riboflavin primarily in the context of fatty acid oxidation (20). It appears likely that they are taken up rapidly by other tissues, including liver which demonstrated a perfectly reciprocal pattern of both flavin and biliverdin levels in the same species (32).…”

The modest impact of transcription factor Nrf2 on the course of disease in an ALS animal model

“…HO-1 is highly inducible by various pro-oxidant and other stressors. 25 Upregulated HO-1 expression has been found in the brain of patients with AD, 26 and in the lumbar spinal cord of SOD1-G93A transgenic mice. 15 NQO1, a redox-regulated flavoenzyme, is sensitive in monitoring cellular redox state.…”

Schizophrenia-Like Features in Transgenic Mice Overexpressing Human HO-1 in the Astrocytic Compartment

“…Mammalian cells express an inducible isoform, HO-1, and constitutively active HO-2. Basal HO-1 expression and activity are maintained at low levels in the normal brain and are restricted to neuroglia and small groups of scattered neurons (Schipper et al, 2009a). Numerous consensus sequences in the HMOX1 promoter render the gene exquisitely sensitive to induction by an array of prooxidant, inflammatory and other noxious stimuli implicated in AD, Parkinson's disease (PD), and schizophrenia (Schipper et al, 2009a;Brown, 2011).…”

“…Biliverdin is further catabolized to the bile pigment bilirubin by biliverdin reductase (Schipper et al, 2009a). Mammalian cells express an inducible isoform, HO-1, and constitutively active HO-2.…”