Based on the in vitro findings summarized

Based on the in vitro findings summarized here, we posited that, in the intact brain, release of ROS from iron-laden astrocytes to the local neuropil elicits oxidative damage and degeneration of indigent dopaminergic projections and other vulnerable neuronal elements (Schipper, 2001). Of particular interest to PD (see Section 8), the pro-toxin, MPTP can be oxidized in astrocytes non-enzymatically (i.e. in the presence of monoamine oxidase inhibitors) to the DA neurotoxin, MPP + by iron and possibly other transition metals (Di Monte et al., 1995). MPP+ is extruded from astrocytes and selectively concentrated in DA neurons where it poisons complex I of the electron transport chain. Our observations suggest that PD subjects treated with MAO inhibitors (e.g. l-deprenyl) to block the bioactivation of endogenous DA or environmental MPTP-like pro-toxins may remain vulnerable to dopaminergic neurotoxins synthesized in astrocytes via iron catalysis (ibid.). Finally, bioenergetic insufficiency within astrocytes may compromise uptake of excitotoxic glutamate from the synaptic cleft (Aschner, 2000), GSH biosynthesis and its transfer to neurons, elimination of toxic protein 4112 mg by the ubiquitin-proteasome system (Ciechanover and Brundin, 2003) and other ATP-dependent processes. In support of the former mechanism, fluorocitrate inhibition of astrocytic mitochondrial function enhances the sensitivity of co-cultured neurons to glutamate toxicity (Voloboueva et al., 2007). In striking contrast to the PC12 cells, exposure to DA/H2O2 had minimal effect on the viability of the HMOX1-transfected, sham-transfected and non-transfected astrocytes themselves. The astrocytes likely survived this exposure because (i) they are enriched for antioxidant defences and exhibit robust heat-shock protein responses (e.g. HSP 27, HSP 72, GRP94, αB-crystallin) relative to other neural cell types and (ii) their ability to effectively revert to anaerobic metabolism for their energy needs (Warburg effect) may permit astroglia (but not neurons) to sacrifice a considerable fraction of their mitochondria with minimal consequence (Schipper, 1999). The role of glial HO-1 in the establishment and perpetuation of ‘core’ neuropathology and neuronal injury is summarized in Fig. 3. In Section 7, we review evidence implicating HO-1 and the ‘core’ gliopathy in normal brain aging, reproductive senescence in rodents and the biogenesis of human CA.
HO-1 and brain aging
Alzheimer disease AD is a degenerative dementia featuring unrelenting neuronal loss, reactive astro- and microgliosis and the deposition of neurofibrillary tangles (containing hyperphosphorylated tau), senile plaques (consisting of β-amyloid) and CA in the basal forebrain, hippocampus and association cortices (Selkoe, 1991). Pathological iron deposition, oxidative substrate modifications, mitochondrial deficits and mitophagy (the ‘core’ tetrad – Sections 1 and 5) have been consistently, albeit usually independently, implicated in the pathogenesis of this illness (Beal, 1995; Mattson, 2002; Reichmann and Riederer, 1994). Oxidative stress and bioenergetic insufficiency in AD brain are evidenced by (i) deficiencies in Kreb cycle enzymes and electron transport (Gibson et al., 1998), (ii) a relative abundance of mtDNA deletions and missense mutations (Corral-Debrinski et al., 1994; Tanno et al., 1998) which correlate with levels of free radical damage (Bonilla et al., 1999), (iii) altered mitochondrial structure and turnover (mitophagy) in the diseased tissues (Hirai et al., 2001) and (iv) attenuated cerebral intermediary metabolism (glucose utilization) in positron emission tomography investigations (Fukuyama et al., 1994; Minoshima et al., 1997). In both AD and PD, non-neuronal (glial and endothelial) cellular compartments exhibit pathological iron deposition and enhanced production of ferritin, the major intracellular iron storage protein (Schipper, 1998b). Increased glial iron was also evident in preclinical AD and mild cognitive impairment patients (MCI), a frequent harbinger of impending Alzheimer dementia (Smith et al., 2010). The transferrin route of iron mobilization utilized by most systemic tissues contributes minimally to the aberrant sequestration of brain iron in these neurodegenerative states as densities of transferrin binding sites are unaltered or vary inversely with levels of stored iron in the affected regions (Schipper, 1999). The latter realization prompted several groups to investigate alternative mechanisms for aberrant iron sequestration in the aging and degenerating CNS, including potential participation of melanotransferrin (p97), lactoferrin (Jefferies et al., 1996, Schipper, 1998a, Schipper, 1999) and HO-1 (Section 8.1).