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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 2014 Aug 21;78(3):441–453. doi: 10.1111/bcp.12357

Oxidative stress, redox signalling and endothelial dysfunction in ageing-related neurodegenerative diseases: a role of NADPH oxidase 2

Sarah Cahill-Smith 1, Jian-Mei Li 1,✉
PMCID: PMC4243896  PMID: 25279404

Abstract

Chronic oxidative stress and oxidative damage of the cerebral microvasculature and brain cells has become one of the most convincing theories in neurodegenerative pathology. Controlled oxidative metabolism and redox signalling in the central nervous system are crucial for maintaining brain function; however, excessive production of reactive oxygen species and enhanced redox signalling damage neurons. While several enzymes and metabolic processes can generate intracellular reactive oxygen species in the brain, recently an O2−-generating enzyme, NADPH oxidase 2 (Nox2), has emerged as a major source of oxidative stress in ageing-related vascular endothelial dysfunction and neurodegenerative diseases. The currently available inhibitors of Nox2 are not specific, and general antioxidant therapy is not effective in the clinic; therefore, insights into the mechanism of Nox2 activation and its signalling pathways are needed for the discovery of novel drug targets to prevent or treat these neurodegenerative diseases. This review summarizes the recent developments in understanding the mechanisms of Nox2 activation and redox-sensitive signalling pathways and biomarkers involved in the pathophysiology of the most common neurodegenerative diseases, such as ageing-related mild cognitive impairment, Alzheimer’s disease and Parkinson’s disease.

Keywords: ageing, Alzheimer’s disease, mild cognitive impairment, NADPH oxidase 2, Parkinson’s disease, redox signalling

Introduction

With a growing ageing population, the number of people with neurodegenerative diseases is steadily increasing 1. Ageing-related neurodegenerative diseases are a group of diseases characterized by the progressive loss of neurons, leading to dysfunction of the central nervous system, and include Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease 2–5. According to the World Health Organization, there are nearly 35.6 million people living with dementia, and this number is expected to double by 2030. Although the exact mechanisms behind the damage and loss of neurons in these detrimental diseases remain unknown, increasing evidence has suggested that an ageing-associated increase in the production of reactive oxygen species (ROS) causes central nervous system oxidative stress, microvascular dysfunction and neuronal damage 6,7.

ROS include both free radicals, e.g. superoxide (O2⋅−) and the hydroxyl radical (OH•), and nonradicals, e.g. hydrogen peroxide (H2O2) 8. ROS can be produced by a number of different means, including mitochondria 9, uncoupled nitric oxide (NO) synthase 10, xanthine oxidase 11 and NADPH oxidase 12. They are short lived and can react quickly with biomolecules to alter their activities. Low levels of intracellular ROS are now recognized to have an important role in the maintenance of normal cellular function and redox signalling 13. However, an excess of ROS results in oxidative stress, which involves damage to cellular components, such as lipids, proteins and nucleic acids, and leads to the loss of biological function 13. Although there are several enzymes and metabolic processes that can generate intracellular ROS, recently an O2⋅−-generating enzyme called NADPH oxidase 2 (Nox2), which is constitutively expressed in a variety of cell types in the brain, including cerebral vascular endothelial cells, has emerged as a major source of oxidative stress in ageing-related neurodegenerative diseases.

The vascular endothelium is a major target of oxidative stress, and there is a close link between vascular endothelial dysfunction and cognitive impairment 14–17. Nox2 is highly expressed in the endothelium, and endothelial oxidative stress due to Nox2 activation in response to environmental challenges increases cerebrovascular permeability and promotes leucocyte adhesion and central nervous system inflammation. Indeed, altered microvascular endothelial function has been recognized as a key factor of advanced ageing and cognitive impairment 14–17. Several previous reviews have discussed the importance of oxidative stress in the biology of ageing 18–20; therefore, the present review focuses on the recent development in understanding the mechanism of Nox2 activation, as well as the role of Nox2-derived oxidative stress and redox signalling in the development of age-related neurodegenerative diseases, such as mild cognitive impairment (MCI), Alzheimer’s disease and Parkinson’s disease.

Mechanism of Nox2 activation and the principle of Nox2 redox signalling

Nox2 (a multicomponent enzyme) was originally discovered in circulating phagocytic cells 21. It consists of a membrane-bound catalytic core called flavocytochrome b558, consisting of gp91phox (β subunit), p22phox (α subunit) and several cytosolic regulatory subunits called p40phox, p47phox, p67phox and rac1 22. Nox2 is normally dormant in resting phagocytes, but when facing a pathogen challenge (or phagocyte activation) the cytosolic subunits translocate to the membrane and associate with cytochrome b558 to activate gp91phox. Activated gp91phox then uses NADPH as an electron donor to convert molecular oxygen to O2⋅− (so-called oxidative burst) and to eliminate the pathogen 23. In the past 15 years, several homologues of gp91phox have been identified and renamed Nox to represent NADPH oxidase. Presently, the Nox family includes seven members (Nox1–5 and Duox 1–2), with the original phagocytic gp91phox being named Nox2. Each Nox is encoded for by a separate gene 8. In this review, Nox2 refers to the NADPH oxidase complex containing gp91phox as the catalytic subunit. Nox1 was initially found in colonic epithelial cells 24, Nox3 is highly expressed in the inner ear 25, Nox4 was first identified in the kidney 26,27, Nox5 is primarily expressed in testis, spleen and lymph nodes 28, and Duox1 and Duox2 are primarily expressed in the thyroid gland 29,30.

Vascular tissue is rich in Nox isoforms. For example, Nox1 is highly expressed in smooth muscle cells, Nox2 is highly expressed in endothelial cells, and Nox4 and Nox5 are detected in both smooth muscle and endothelial cells 31,32. The central nervous system also expresses Nox isoforms, with Nox2 and Nox4 being the most prominent isoforms detected in a variety of cell types, including neurons, microglia and astrocytes 33–37. Among these Nox isoforms, Nox2 has been shown to be an important source of O2⋅− production in cerebral arteries 38 and plays a major role in cerebrovascular diseases 39. In a mouse model of stroke, treatment with apocynin or deletion of Nox2 reduced infarct volume in the cortex and subcortex after cerebral ischaemia–reperfusion in association with reduced O2⋅− production 40,41. However, in the absence of reperfusion, ROS production by Nox2 seemed not to have a significant role in the pathophysiology of cerebral ischaemia 42.

Although Nox2 in nonphagocytic cells shares structural similarity with the phagocytic Nox2, the regulatory mechanism of Nox2 activation in nonphagocytic cells is completely different from that in phagocytic cells 43. We have reported that Nox2 in resting endothelial cells is already partly pre-assembled and continuously generates very low levels of O2⋅−, which is involved in redox regulation of normal cellular functions 43,44. Phosphorylation of the p40phox subunit has been found to be involved in maintaining the basal Nox2 activity in nonphagocytic cells 45. However, Nox2 in nonphagocytic cells can respond to a variety of stimulants to become activated and cause oxidative stress to cells and organs. Rac1 regulation of Nox2 activity and protein phosphorylation represent two of the important mechanisms in Nox2 activation 46,47. Our recent studies have shown that serine phosphorylation of p47phox is a prerequisite for Nox2 activation in response to stimulation by tumour necrosis factor α (TNFα) 48,49, angiotensin II 50,51 and the protein kinase C activator phorbol 12-myristate 13-acetate 49. Furthermore, we have discovered that the phosphorylation of p47phox at serine residues S303, S304 and S379 plays a vital role in initiating Nox2 activation and O2⋅− production under pathological conditions 52.

In response to cellular challenges, such as growth factors, inflammatory cytokines, cell stress such as ischaemia–reperfusion and cytotoxic reagents, Nox2 is activated, and the resulting increase in O2⋅− production plays a key role in somatic cellular senescence and ageing 53–55. In terms of central nervous system inflammation, Nox2 in microglial cells (the phagocytes in the brain) is activated in response to neurotoxic stimulation, and excessive ROS production causes neuronal damage. However, microglial cells can respond to neuronal damage and become further activated. This activation can be long lived, self perpetuating and eventually kill the neuron 37.

The primary product of Nox2 is O2⋅−, which is short lived and can react with several different molecules to form other ROS, such as H2O2, OH•, hypochlorous acid (HOCl) and peroxynitrite (ONOO−) 8. Therefore, it is possible that Nox2 redox signalling occurs through these secondary products rather than through O2⋅− itself 13. Most proteins involved in cellular signalling contain cysteine residues or protein-bound metals, which are targets of ROS modification 56. Thiol chemistry plays an important role in maintaining cellular redox homeostasis and therefore plays a key role in directing the redox signalling pathways 13. Redox signalling involves both reversible and irreversible protein reactions. A good example of a reversible reaction is protein phosphorylation and dephosphorylation, and a lot of protein kinases and phosphatases are redox-sensitive targets (for details see end of paragraph). ROS-induced irreversible reactions include protein degradation or protein S-nitrosylation. Oxidation of lipids, proteins, DNA bases and the sugar backbones of DNA and RNA are mainly irreversible 13. In terms of neurodegeneration, protein S-nitrosylation has been reported to be involved in redox-mediated post-translational modification of proteins and causes synaptic damage and brain cell death 57. Recent studies from others and ourselves have found that the most common downstream targets of Nox2-derived ROS are mitogen-activated protein kinases (MAPKs), such as the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK 48,52,58,59; protein kinase B 60–63; phosphoinositide 3-kinase 64; nuclear factor κB (NFκB) 65; TNFα receptor-associated factor 4 48; and signalling molecules involved in cell apoptosis, such as p21cip1 and p53 66.

Oxidative stress and redox signalling in ageing-related mild cognitive impairment

Oxidative stress has been seen to play a major role in the mammalian ageing process and is the result of an imbalance between pro-oxidant and antioxidant levels. There has been extensive research looking at levels of various oxidative stress biomarkers during ageing; for example, protein carbonyls to detect protein oxidation 67–69, malondialdehyde (MDA) to detect lipid peroxidation 68,70,71 and 8-hydroxy-2’-deoxyguanosine to detect DNA oxidation 72,73. Levels of tissue ROS have also been found to increase with ageing 74,75, along with decreases in various antioxidants, such as vitamins A and C, and antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase 76–78.

During the normal ageing process, a progressive decline in cognitive function linked with multi-organ oxidative stress has been observed in numerous experimental studies, implicating that cognitive impairment may be associated with ageing-related oxidative damage in the brain. For example, increased O2⋅− production in the brain was found in ageing mice (24 months old) in association with significant cognitive impairment 74. More recently, another study reported increases in ROS production, lipid peroxidation and nucleic acid oxidation in ageing mice (23 months old) in correlation with a decline in learning and memory 72. A high-fat lard diet further exacerbated cognitive decline in aged mice (24 months old), and this was associated with high levels of oxidative stress in the hippocampus 79.

Mild cognitive impairment (MCI) is generally characterized as a memory deficit abnormal for the individual’s age. Clinical diagnosis criteria include the following: (i) memory complaint, preferably corroborated by an informant; (ii) objective memory impairment for age and education; (iii) normal general cognitive function; (iv) intact activities of daily living; and (v) no evidence of dementia 80. MCI is generally seen as a transitional state between normal cognitive ageing and dementia and is frequently associated with the development of Alzheimer’s disease, with annual conversion rates of MCI to Alzheimer’s disease of ∼10–15% 81,82. Ageing is a strong risk factor for both MCI and Alzheimer’s disease, with prevalence for MCI estimated to be 1% at age 60 years and increase to 42% by age 85 years and prevalence for Alzheimer’s disease estimated to be 1% at age 60 years and increase to 25% by age 85 years 83. As previously mentioned, age-related increases in oxidative stress have been widely reported, and evidence is emerging for the role of oxidative stress in the pathogenesis of MCI and Alzheimer’s disease.

High levels of oxidative stress related to cognitive decline have been observed. For example, in patients with MCI, increases in protein carbonyl content and MDA were found in the superior and middle temporal gyri, which were indicative of protein oxidation and lipid peroxidation, respectively 84. Increased peripheral MDA has been found in erythrocytes, serum and plasma 85–87 of patients with MCI. Other markers of lipid peroxidation include: the isoprostane 8,12-iso-iPF2α-VI, which has been found to be significantly increased in the plasma, cerebrospinal fluid and urine of MCI patients 88; lipid hydroperoxide, which has been found to be increased in the serum of MCI patients 89; and 4-hydroxy-2-nonenal, which has been found to be increased in the hippocampus and inferior parietal lobules of MCI patients 90.

Nitrosative stress is also seen in ageing. Increased 3-nitrotyrosine levels were found in the hippocampus and inferior parietal lobule of aged patients (88 ± 3.8 years old) with MCI, which is indicative of protein nitration 91. One of the major causes of protein nitration is the reaction with peroxynitrite, which is a potent oxidizing and nitrating agent produced by the reaction of superoxide and nitric oxide. Increased expression of inducible nitric oxide synthase has been found with ageing in mice (22 months old), which led to increased levels of nitric oxide that can react readily with the abundant superoxide present 92.

MCI is associated not only with an increase in pro-oxidants, but also with a decrease in antioxidants. Several studies have shown a decrease in levels of non-enzymatic antioxidants, including vitamins A, C and E and uric acid, and a decrease in activity of antioxidant enzymes, including superoxide dismutase and glutathione peroxidase, in serum and plasma of patients with MCI 93–95. In fact, a report has found a direct correlation between antioxidant depletion and cognitive deterioration 86.

Nox2 is a major source of oxidative stress involved in the development of ageing-related MCI. Nox2 expression has been found to be increased in the superior and middle temporal gyri of patients with MCI and in the brain of ageing mice (23 months old) 96,97. Aged mice overexpressing the amyloid precursor protein (12–15 months old) exhibited signs of cognitive decline and had significantly increased levels of Nox2-derived superoxide production in the brain 98. There is a linear relationship between cognitive decline and Nox2 activity 99,100. Moreover, increased expression of the Nox2 subunits p47phox and p67phox has also been reported in the temporal cortex of MCI patients, which again correlated strongly with a decline in cognition 101. These findings strongly support a substantial role for Nox2-derived oxidative stress in the development of cognitive impairment.

Oxidative stress and redox signalling in Alzheimer’s disease

Alzheimer’s disease is the most common form of dementia and is characterized by progressive memory loss, cognitive impairment, aphasia (language disturbance), apraxia (impaired ability to carry out motor activities despite intact motor function), agnosia (failure to recognize or identify objects despite intact sensory function) and disturbance in executive functioning (i.e. planning, organizing, sequencing and abstracting) 102,103. Alzheimer’s disease is associated with accumulation of amyloid plaques and neurofibrillary tangles constituted by highly phosphorylated tau proteins in the brain, and the loss of neurons from the hippocampus and cerebral cortex 104. Nox2 activation in brain tissue and Nox2-derived oxidative damage has emerged as an important mechanism in the pathogenesis of Alzheimer’s disease 105,106.

Alzheimer’s disease is strongly linked with accumulation of the protein β-amyloid, and there is a close relationship between the levels of β-amyloid and Nox2 activity 100,107. Cerebral amyloid angiopathy characterized by deposition of β-amyloid in the cerebrovasculature is present in 80–100% of Alzheimer’s disease cases 108. β-Amyloid is toxic to brain endothelial cells, leading to the loss of blood–brain barrier integrity. Increased expression of Nox2 and oxidative stress were found in activated microglia surrounding β-amyloid-laden capillaries from patients with capillary cerebral amyloid angiopathy 108,109. In addition, neuronal cell viability was shown to be significantly decreased in the presence of β-amyloid, and this effect was attenuated in the presence of a Nox2 inhibitor, apocynin 97. However, it is important to note that it is still disputable whether the mode of action of apocynin is as an antioxidant or as a Nox2 inhibitor 110–114. Apocynin has been shown to have a neuroprotective effect in mouse models of ischaemia and amyotrophic lateral sclerosis; however, in a model of Alzheimer’s disease it did not improve behavioural or neuropathological deficits despite causing a reduction in oxidative stress in the cerebral cortex 115–117. In a mouse model of Alzheimer’s disease with overexpression of the amyloid precursor protein, the level of superoxide production in the brain was significantly increased in association with neurovascular dysfunction and behavioural deficits, and these were significantly attenuated in mice with Nox2 deficiency 98. Nox2-derived oxidative stress has also been found to play a major role in mediating β-amyloid protein-induced neuronal death and neurovascular dysfunction 118,119.

A variety of stimuli, such as bacterial components, inflammatory cytokines, β-amyloid peptide and other neurotoxins, have been shown to activate Nox2 and induce ROS production in brain tissue 37,120. Increased ROS production activates downstream signalling pathways, such as ERK1/2 and the phosphorylation of cytosolic phospholipase A2α 121. Overactivation of cytosolic phospholipase A2α is believed to contribute to the pathogenesis of a number of neurodegenerative diseases, including Alzheimer’s disease 122. Other redox-sensitive MAP kinases, such as p38 MAPK, have also been found to be upregulated in the brains of patients with Alzheimer’s disease 123. More recently, an increase in the expression of p53, a redox-sensitive apoptosis-related molecule, has been found in the brain tissue of patients with Alzheimer’s disease, and this was associated with increased nitric oxide synthase and Nox1 and Nox3 expression 124. The amyloid precursor protein involved in Alzheimer’s disease pathogenesis has been seen rapidly to activate JNK, ERK and p38 MAPK in rat microglial cells in association with increased inducible nitric oxide synthase expression 125. Stimulation of rat pheochromocytoma (PC12) cells with β-amyloid activated the NFκB, ERK and p38 MAPK pathways, which was associated with increases in intracellular ROS production, the levels of expression of apoptotic proteins p53, Bcl-2-associated X protein and caspase-3, and downregulation of the anti-apoptotic protein Bcl-2 126. β-Amyloid has also been found to activate the NFκB pathway by selectively inducing the nuclear translocation of p65 and p50 subunits in human neurons 127.

Oxidative stress and redox signalling in Parkinson’s disease

Parkinson’s disease is a movement disorder characterized by bradykinesia, rigidity, resting tremor and postural instability and is associated with the progressive loss of dopaminergic neurons from the substantia nigra region in the midbrain 15,128,129. The aetiology and underlying mechanisms of Parkinson’s disease are still under investigation but increasing evidence is emerging for the involvement of Nox2-derived ROS and oxidative stress. Ageing is a strong risk factor for oxidative stress and the development of Parkinson’s disease. Nox2 is highly expressed in microglial cells [130] and to a lesser extent in dopaminergic neurons [33]. Nox2 has been found along with degeneration of dopaminergic neurons and is implicated in the development of Parkinson’s disease [131], [132].

Several studies carried out in mice have used administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which selectively destroys the nigrostriatal dopaminergic pathway, as a model of Parkinson’s disease 131,133–135. One such study showed that Nox2 expression was upregulated both in MPTP-treated mice and in patients with Parkinson’s disease, indicating a crucial role of Nox2 in the MPTP-induced loss of dopaminergic neurons 133. A ROS scavenger, ethyl pyruvate, was found to improve MPTP-induced motor deficits by attenuating Nox2 activation, ROS production, microglial activation and neuronal loss. The mechanism involved was found to be in part due to the inhibition of p47phox phosphorylation and the subsequent binding of p47phox to gp91phox 134.

Studies of other mouse models have also been carried out, and a transgenic mouse model of Parkinson’s disease has recently been created with mutations in leucine-rich repeat kinase 2 (LRRK2), which is the most common genetic cause of Parkinson’s disease. These LRRK2R1441G transgenic mice exhibit the key characteristics of Parkinson’s disease, including age-dependent and levodopa-responsive slowness of movement along with impaired dopamine release 136. A recent study found that treatment of these transgenic mice with diapocynin, a Nox2 inhibitor, alleviated symptoms of early Parkinson’s disease; in particular, motor co-ordination and balance 137. However, due to the high concentration of diapocynin required to inhibit hydroethidine oxidation to 2-hydroxyethidium, the exact mechanism behind the effects of diapocynin in these mice remains unknown 137. As mentioned previously, the mechanism of apocynin and diapocynin action needs further investigation.

The molecular mechanisms regulating dopaminergic neuronal cell death are not yet fully understood, but evidence suggests an important role of ROS. Increased ROS production and MAPK activation, including p38 MAPK and ERK1/2, has been seen to be involved in dopaminergic cell death 138. In an experimental model of Parkinson’s disease, increased phosphorylation of JNK and p38 MAPK was evident as well as increased apoptosis in human dopaminergic SH-SY5Y cells 139. Likewise, activation of ERK1/2, JNK and p38 MAPK was found in brains of patients with Parkinson’s disease 140. In the MPTP animal model of Parkinson’s disease, increased levels of JNK and MKK4 phosphorylation were found to be associated with activation of apoptosis signal-regulating kinase 1 and a decrease in DJ-1, the Parkinson’s disease-associated neuroprotective protein 141,142. MAPK-activated protein kinase-2 (MK2) is a downstream target of p38 MAPK. A recent study has shown that neurodegeneration can be prevented in a mouse model of lipopolysaccharide-induced Parkinson’s disease by eliminating MK2 143. In that study, it was also discovered that increased production of inflammatory mediators, such as TNFα, keratinocyte-derived chemokine, interleukin-6 and nitric oxide, with lipopolysaccharide administration was associated with decreased levels of tyrosine hydroxylase-positive neurons, and this was attenuated in MK2−/− mice 143. In mice treated with MPTP, p38 MAPK activation was found to induce p53 phosphorylation and nuclear translocation, and this subsequently increased activity of the p53-upregulated modulator of apoptosis and Bcl-2-associated X protein 144. Inhibition of p53 activity improved motor function, reduced damage to nigrostriatal dopaminergic neurons and prevented the increase in Bcl-2-associated X protein in MPTP-treated mice, and this in turn protected against MPTP-mediated cell death in human primary neurons 144,145. Put together, these data strongly support the pivotal roles for Nox2 and oxidative activation of p53 in the pathophysiology of Parkinson’s disease.

Conclusion

The pathophysiology of the most common neurodegenerative diseases, such as ageing-related MCI, Alzheimer’s disease and Parkinson’s disease, involves multiple factors that cause the deterioration of the central nervous system throughout the ageing process. Existing endothelial dysfunction and metabolic disorders contribute to the exacerbation of the clinical symptomatology. Although precise cellular and molecular mechanisms underlying these diseases are still largely unknown, oxidative stress due to the activation of Nox2 in the neurovascular endothelium, microglia, neurons and other brain cells represents one of the key features and common determinants responsible, at least in part, for the pathological process of these diseases. Figure 1 is a schematic summary of factors discussed in this review that are involved in the pathogenesis of common neurodegenerative diseases. The redox signalling pathways discussed in this article are listed in Table 1 for experimental animal studies and in Table 2 for clinical human studies. Understanding the mechanism of Nox2 activation and its redox signalling pathways will help the discovery of novel specific drug targets to slow down the progress and, eventually, to treat these detrimental neurodegenerative diseases.

Figure 1.

Figure 1

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Schematic summary of factors involved in the brain oxidative stress and oxidative biomarkers in the pathogenesis of neurodegenerative diseases. Abbreviations are as follows: 3-NT, 3-nitrotyrosine; 4-HNE, 4-hydroxynonenal; 8,12-iso-iPF2α-VI, isoprostane; APP, amyloid precursor protein; IL-1α, interleukin-1 alpha; IL-1β, interleukin-1 beta; IL-6, interleukin-6; IL-12, interleukin-12; MDA, malondialdehyde; TBARS, thiobarbituric acid reactive substance; TNFα, tumour necrosis factor alpha

Table 1.

Redox signalling pathways in mouse models of neurodegenerative diseases

Strain Model Signalling pathways examined Reference
SAMP8 Ageing MDA, NO, GPx 146
C57Bl/6N Sim Ageing MDA, 8-OHdG 72
C57Bl/6 HFLD Protein carbonyl 79
SAMP8 Ageing Protein carbonyl, TBARS 147
C57Bl/6N Sim Ageing Protein carbonyl, MDA 148
Balb/C Ageing GSH 149
FVB/N Tg2576 8,12-iso-iPF2α-VI 150
C57BL/6J LPS TNFα, IL-1β, Iba-1, MCP-1 132
C57BL/6J MPTP iNOS, 3-NT, 4-HNE 151
C57BL/6J MPTP MAC-1, Iba-1, ED-1, 8-OHdG, 3-NT, iNOS, MPO 134
C57BL/6J LPS TNFα, IL-6, KC, IL-12, NO, nitrite, p-p38 143
C57BL/6J MPTP MAC-1, iNOS, TNFα 143
C57BL/6J MPTP iNOS, IL-1β, TNFα, CD11b, GFAP, NF-κB 152
C57BL/6J MPTP ASK1, p-MKK4, p-JNK, GSH, Daxx, DJ-1 142
C57BL/6J MPTP 4-HNE, 3-NT, GSH, GSSG 135
C57BL/6J MPTP Nitrite 131
C57BL/6J MPTP MAC-1, protein carbonyl 133
C57BL/6 MPTP Bax, p53 145
C57BL/6J MPTP p-JNK, p-MKK4 141
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3-NT, 3-nitrotyrosine; 4-HNE, 4-hydroxynonenal; 8,12-iso-iPF2α-VI, isoprostane; 8-OHdG, 8-Hydroxy-2′-deoxyguanosine; ASK1, apoptosis signal-regulating kinase 1; Bax, Bcl-2-associated X protein; CD11b, cluster of differentiation molecule 11b; Daxx, death-associated protein; DJ-1, Parkinson’s disease protein; ED-1, clone ED1 CD68 microglial/macrophage marker; GFAP, glial fibrillary acidic protein; GPx, glutathione peroxidise; GSH, glutathione; GSSG, oxidized glutathione; HFLD, high fat lard diet; Iba-1, ionized calcium binding adapter molecule 1; IL-1β, interleukin-1 beta; IL-6, interleukin-6; IL-12, interleukin-12; iNOS, inducible nitric oxide synthase; KC, keratinocyte-derived chemokine; LPS, lipopolysaccharide; MAC-1, macrophage antigen complex-1; MCP-1, monocyte chemoattractant protein-1; MDA, malondialdehyde; MPO, myeloperoxidase; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NFκB, nuclear factor kappa B; NO, nitric oxide; p-MKK4, phospho-dual specificity mitogen-activated protein kinase kinase 4; p-JNK, phospho-c-jun N-terminal kinase; p-p38, phospho-p38 mitogen-activated protein kinase; p53, tumour suppressor protein; TBARS, thiobarbituric acid reactive substance; Tg2576, mouse model of Alzheimer’s disease amyloidosis; TNFα, tumour necrosis factor alpha.

Table 2.

Redox signalling pathways in human neurodegenerative diseases

Diagnosis Signalling pathways examined Ref.
MCI LPO 89
MCI MDA 87
MCI MDA, GPx, catalase 85
MCI SOD, GPx, MDA 95
MCI MDA, nitrite and nitrate, GSSG 86
MCI 3-NT 91
MCI Protein carbonyl 153
MCI 4-HNE 90
MCI Protein carbonyl, TBARS, MDA 84
MCI Vitamins A, C and E, uric acid, SOD, GPx 94
MCI 8,12-iso-iPF2α-VI 88
Alzheimer’s disease MDA 87
Alzheimer’s disease MDA, GPx, catalase 85
Alzheimer’s disease SOD, GPx, MDA 95
Alzheimer’s disease MDA, nitrite and nitrate, GSSG 86
Alzheimer’s disease iNOS, eNOS, nNOS, p53, UCP2,4,5, mitochondrial complexes I–V, PPARα, δ, γ 124
Alzheimer’s disease 3-NT 154
Alzheimer’s disease Protein carbonyl, TBARS, MDA 84
Alzheimer’s disease 8-OH-adenine, 5-OH-cytosine, 5-OH-uracil, 8-OH-guanine 155
Alzheimer’s disease 3-NT 156
Alzheimer’s disease Vitamin A, C and E, uric acid, SOD, GPx 94
Alzheimer’s disease 8,12-iso-iPF2α-VI 88
Alzheimer’s disease p-p38 123
Parkinson’s disease 8-OHdG 157
Parkinson’s disease p-p38, p-JNK 144
Parkinson’s disease NF-κB 152
Parkinson’s disease p-Src, p-HSP27, p-JNK 158
Parkinson’s disease Glutathione reductase 159
Parkinson’s disease TBARS 160
Parkinson’s disease p-ERK1/2, p-p38, p-JNK 140
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3-NT, 3-nitrotyrosine; 4-HNE, 4-hydroxynonenal; 8,12-iso-iPF2α-VI, isoprostane; 8-OHdG, 8-Hydroxy-2′-deoxyguanosine; eNOS, endothelial nitric oxide synthase; GPx, glutathione peroxidise; GSSG, oxidized glutathione; iNOS, inducible nitric oxide synthase; LPO, lipid hydroperoxide; MCI, mild cognitive impairment; MDA, malondialdehyde; NFκB, nuclear factor kappa B; nNOS, neuronal nitric oxide synthase; p-ERK, phospho-extracellular signal-regulated kinase; p-HSP27, phospho-heat shock protein 27; p-JNK, phospho-c-jun N-terminal kinase; p-p38, phospho-p38 mitogen-activated protein kinase; p-Src, phospho-proto-oncogene tyrosine-protein kinase; p53, tumour suppressor protein; PPAR, peroxisome proliferator-activated receptor; SOD, superoxide dismutase; TBARS, thiobarbituric acid reactive substance; UCP, uncoupling protein.

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: SC-S had support from Age UK for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

Sarah Cahill-Smith was supported by an RIA research scholarship from Age UK.

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