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Plasma oxidative stress parameters in men and women with early stage Alzheimer type dementia

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... Both MCI and AD patients show increased plasma levels of advanced oxidation protein products (Chico et al., 2013). Increased carbonyl groups content in the plasma of early AD subjects have been reported (Puertas et al., 2012). Carbonyl proteins in the plasma can be roughly three times higher in MCI/AD relative to the age-matched healthy controls (Greilberger et al., 2010; Table 1). ...
... The plasma, CSF, and urine of MCI subjects exhibit higher levels of isoprostane 8,12-iso-iPF(2alpha)-VI, a marker of in vivo lipid peroxidation, as compared to cognitively normal elderly controls (Pratico et al., 2002). Plasma and whole blood levels of thiobarbituric acid reactive substances, an index of lipid peroxidation, are likewise high in early AD (Puertas et al., 2012;Martinez de Toda et al., 2019). Lipid hydroperoxides are the unstable products of lipid peroxidation that undergo non-enzymatic decomposition to generate aldehydes like malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE); latter form covalent adducts to alter physiological proteins. ...
... In addition to oxidative damage, reduced antioxidant defenses have been reported in MCI and early AD (Rinaldi et al., 2003;Baldeiras et al., 2010;Chico et al., 2013). Plasma glutathione levels and antioxidant enzymes such as glutathione peroxidase, catalase, and superoxide dismutase (SOD) are significantly decreased in early AD (Torres et al., 2011;Puertas et al., 2012). Apolipoprotein E4 (APOE4) is the major genetic risk factor in AD. ...
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Oxidative stress (OS) contributes towards Alzheimer’s disease (AD) pathology. OS can be a result of increased reactive oxygen/nitrogen species, reduced antioxidants, oxidatively damaged molecules and/or a combination of these factors. Scientific literature is scarce for the markers of OS specific for detecting AD at an early stage. The first aim of the current review is to highlight potential OS markers in the brain, cerebrospinal fluid, blood and/or urine that can be used for early diagnosis of human AD. The reason for exploring OS markers is that the proposed antioxidant therapies against AD appear to start too late to be effective. The second aim is to evaluate the evidence for natural antioxidants currently proposed to prevent or treat AD symptoms. To address these two aims, we critically evaluated the studies on humans in which various OS markers for detecting AD at an early stage were presented. Non-invasive OS markers that can detect mild cognitive impairment and AD at an early stage with greater specificity and sensitivity are primarily related to lipid peroxidation. However, a combination of OS markers, family history and other biochemical tests are needed to detect the disease early on. We also report that the long-term use of vitamins (vitamin E as in almonds) and polyphenol-rich foods (curcumin/curcuminoids of turmeric, gingko biloba, epigallocatechin-3-gallate in green tea) seem justified for ameliorating AD symptoms. Future research on humans is warranted to justify the use of natural antioxidants.
... For example, in AD plasma samples GPx activity was found lower compared to controls (Puertas et al., 2012). This alteration can be detected also early in the disease stage from MCI patients (Padurariu et al., 2010;Rinaldi et al., 2003). ...
... However, when GPx activity was measured in erythrocytes from MCI and AD patients, an increase in AD was found while no changes were observed in patients with MCI. Opposites between plasma and erythrocytes have also been found for catalase activity, reported a reduction in plasma of patients with early-stage dementia (Puertas et al., 2012) and an increase in erythrocytes in patients with AD. Differences were also highlighted between the intracellular and extracellular blood compartment, as suggested by our previous findings. ...
... Differences were also highlighted between the intracellular and extracellular blood compartment, as suggested by our previous findings. In particular, Arce-Varas et al. (Arce-Varas et al., 2017) showed a reduction in SOD and CAT, while in contrast to Puertas et al. (Puertas et al., 2012), an increase in GPx activity was found in both AD and MCI plasma compared to controls. Indeed, in blood peripheral mononuclear cells from both AD and MCI, only SOD activity was found affected. ...
Article
Several theories have been postulated, trying to explain why and how living organisms age. Despite some controversies and still huge open questions, a growing body of evidence suggest alterations of mitochondrial functionality and redox-homeostasis occur during the ageing process. Oxidative damage and mitochondrial dysfunction do not represent the cause of ageing per se but they have to be analyzed within the complexity of those series of processes occurring during lifespan. The establishment of a crosstalk among them is a shared common feature of many chronic age-related diseases, including neurodegenerative disorders, for which ageing is a major risk factor. The challenge is to understand when and how the interplay between these two systems move towards from normal ageing process to a pathological phenotype. Here in this review, we discuss the crosstalk between mitochondria and cytosolic-ROS. Furthermore, through a visual data mining approach, we attempt to describe the dynamic interplay between mitochondria and cellular redox state on the route from ageing to an AD phenotype
... Recent research has shown an increasing interest in the clinical validation of potential biomarkers to early and specific diagnose AD using minimally invasive biological samples [35]. Among the physiological mechanisms that are already impaired in early disease stages, lipid peroxidation has shown some promising results, and plasma samples constitute an interesting matrix in the search for the corresponding biomarkers [16,[36][37][38][39][40][41][42]. ...
... Among lipid peroxidation biomarkers evaluated in plasma, some AD studies found altered levels for malondialdehyde [36][37][38]42], 4-hydroxynonenal [39], lipophilic fluorescent products [40,41], and isoprostanes [4]. In general, these potential biomarkers showed elevated levels in AD in comparison with healthy participants, reflecting high oxidative stress at systemic level. ...
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Background: Differential diagnosis of Alzheimer's disease (AD) is a complex task due to the clinical similarity among neurodegenerative diseases. Previous studies showed the role of lipid peroxidation in early AD development. However, the clinical validation of potential specific biomarkers in minimally invasive samples constitutes a great challenge in early AD diagnosis. Methods: Plasma samples from participants classified into AD (n = 138), non-AD (including MCI and other dementias not due to AD) (n = 70) and healthy (n = 50) were analysed. Lipid peroxidation compounds (isoprostanes, isofurans, neuroprostanes, neurofurans) were determined by ultra-performance liquid chromatography coupled with tandem mass spectrometry. Statistical analysis for biomarkers' clinical validation was based on Elastic Net. Results: A two-step diagnosis model was developed from plasma lipid peroxidation products to diagnose early AD specifically, and a bootstrap validated AUC of 0.74 was obtained. Conclusion: A promising AD differential diagnosis model was developed. It was clinically validated as a screening test. However, further external validation is required before clinical application.
... For example, plasma GPX activity has been documented to be higher in patients with Alzheimer's disease (AD) and in those with vascular dementia (VaD) compared to healthy controls in some studies [27][28][29]. Other studies in MCI and AD have found plasma GPX activity decreased compared to age-matched controls [30,31], and another found no significant difference between dementia patients and controls [32]. The heterogeneity in GPX activity across those studies may be due to a variety of factors including the wide ranges in severity of cognitive impairments considered, as well as different sample populations, with no data to date in VCIND. ...
... Given previous reports of increased oxidative stress in VCIND [15] but high heterogeneity in GPX activity across dementias [27,28,30,31], our primary hypothesis was that GPX activity would be increased in possible VCIND participants compared to CN. Our secondary hypotheses were that baseline GPX activity would predict verbal memory, and that change in GPX activity over 6 months would be associated with change in verbal memory. ...
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Background: Coronary artery disease (CAD) increases risk for vascular cognitive impairment-no dementia (VCIND), a precursor to dementia, potentially through persistent oxidative stress. Objective: This study assessed peripheral glutathione peroxidase activity (GPX), which is protective against oxidative stress, in VCIND versus cognitively normal CAD controls (CN). GPX activity was also evaluated as a biomarker of cognition, particularly verbal memory. Methods: 120 CAD patients with VCIND (1SD below norms on executive function or verbal memory (VM)) or without (CN) participated in exercise rehabilitation for 24 weeks. Neurocognitive and cardiopulmonary fitness (VO2peak) assessments and plasma were collected at baseline and 24-weeks. Results: GPX was higher in VCIND compared to CN (F1,119 = 3.996, p = 0.048). Higher GPX was associated with poorer baseline VM (β= -0.182, p = 0.048), and longitudinally with VM decline controlling for sex, body mass index, VO2peak, and education (b[SE] = -0.02[0.01], p = 0.004). Only CN participants showed improved VM performance with increased fitness (b[SE] = 1.30[0.15], p < 0.005). Conclusion: GPX was elevated in VCIND consistent with a compensatory response to persistent oxidative stress. Increased GPX predicted poorer cognitive outcomes (verbal memory) in VCIND patients despite improved fitness.
... (2) PON3 (also antioxidant) [12]; (3) lipoprotein phospholipase A2 (Lp-PLA2, antioxidant) [13]; (4) myeloperoxidase (MPO, prooxidant and proinflammatory) [14]; (5) glutathione peroxidase-3 (GPx-3, antioxidant) [15] and (6) serum amyloid A (SAA, prooxidant, proinflammatory) [16] ( Figure 1). ...
... [110]. The published observational data reported unvaried [51,111] or lower [15,53,55,112] levels of this enzyme in AD patients compared with controls and are summarized in Table 1. In one of the largest population-based studies, Rinaldi et al. found that the activity level of GPx-3 was similarly lower in MCI (n = 25) and AD (n = 63) patients as compared with controls (n = 53) [54]. ...
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The protein composition of high-density lipoprotein (HDL) is extremely fluid. The quantity and quality of protein constituents drive the multiple biological functions of these lipoproteins, which include the ability to contrast atherogenesis, sustained inflammation, and toxic effects of reactive species. Several diseases where inflammation and oxidative stress participate in the pathogenetic process are characterized by perturbation in the HDL proteome. This change inevitably affects the functionality of the lipoprotein. An enlightening example in this frame comes from the literature on Alzheimer’s disease (AD). Growing lines of epidemiological evidence suggest that loss of HDL-associated proteins, such as lipoprotein phospholipase A2 (Lp-PLA2), glutathione peroxidase-3 (GPx-3), and paraoxonase-1 and paraoxonase-3 (PON1, PON3), may be a feature of AD, even at the early stage. Moreover, the decrease in these enzymes with antioxidant/defensive action appears to be accompanied by a parallel increase of prooxidant and proinflammatory mediators, in particular myeloperoxidase (MPO) and serum amyloid A (SAA). This type of derangement of balance between two opposite forces makes HDL dysfunctional, i.e., unable to exert its “natural” vasculoprotective property. In this review, we summarized and critically analyzed the most significant findings linking HDL accessory proteins and AD. We also discuss the most convincing hypothesis explaining the mechanism by which an observed systemic occurrence may have repercussions in the brain.
... Also, eNOS-derived NO can directly modulate the production of amyloid beta (Aß) avoiding its increase [19]. However, NO also acts as a free radical, and an excessive amount of NO, mainly derived from inducible NOS (iNOS), leads to neurotoxicity and neurodegeneration due to nitroxidative stress instead of oxidative stress [14,20,21]. It has been also reported that NO produced in response to Aß promotes mitochondrial fission, synaptic loss, and neuronal damage [22]. ...
... Cognitive and functional status of AD patients was assayed by Mini-Mental State Examination (21.89 ± 0.58); Blessed Scale (6.98 ± 0.46) and Brief Cognitive Rating Scale (BCRS) adapted as Functional Assessment Stage (FAST) (3.80 ± 0.11) [21]. Study participants´ fasting blood samples were collected in the morning and centrifuged immediately. ...
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Background: L-arginine is an amino acid that can be metabolized to form several bioactive molecules including nitric oxide (NO). In the central nervous system (CNS), NO regulates various and important physiological functions. However, the involvement of L-arginine metabolism –and by extension of NO- in Alzheimer’s disease (AD) pathogenesis, has been suggested. Objective: To determine the global L-arginine bioavailability ratio (GABR) and NO levels (as the sum of nitrates and nitrites, NOx) in the plasma of early-stage Alzheimer’s disease (AD) patients in order to analyze if GABR can reflect an altered NO production, to confirm the importance of L-arginine metabolism in the development of the disease, and to evaluate the putative diagnostic/prognostic value of GABR. Method: GABR index is an indicator of the availability of L-arginine to form NO by nitric oxide synthases. It is calculated as the ratio between the levels of L-arginine and the sum of the levels of L-ornithine and L-citrulline. Plasma amino acids are measured by high-performance liquid chromatography coupled to fluorescence detection. Nitric oxide is measured in plasma as the sum of nitrates and nitrites (NOx). Results: No changes were found in L-arginine levels, whereas L-citrulline and L-ornithine levels were highly increased in AD patients. We also found that GABR decreased significantly by 47.8% in AD patients, whereas NOx levels increased significantly by 46.9%. Receiver operator characteristic (ROC) curve analysis for GABR showed a sensitivity of 78.1 and a specificity of 90.5. Conclusion: Low plasma GABR levels in AD patients reflect that the L-arginine-NO pathway has turned towards NO in AD, probably being related to the nitroxidative stress involved in neurodegenerative diseases. Furthermore, increased NOx could also be involved in several altered physiological functions. Therefore, GABR is proposed as a putative useful biomarker of the disease.
... The molecule is a critical component of the body's antioxidant system, and it plays a key role in counteracting oxidative stress, which is also associated with AD [17][18][19][20]. Generally, GSH appears to be depleted throughout the body with age [21], [-] [25] and even more so in AD [26][27][28][29][30][31][32][33]. A body of research has shown that GSH plays a role in intracellular copper chelation [34], [-] [37] and it has often been suggested that GSH-copper binding inhibits the ability of copper to generate ROS, protecting vulnerable cellular components from oxidative stress [38][39][40][41][42][43]. ...
... Regardless, significantly more clinical evidence would be needed to substantiate their interpretation of GPx alteration in NDs. The results from that study, at least as they apply to AD, are currently overshadowed by the large number of studies pointing to overall decreases in serum/plasma GSH in AD [26][27][28][29][30][31][32]. Additionally, a 2013 meta-analysis by Schrag et al. [134] analyzed 9 studies measuring GPx activity in serum, and found no meaningful differences in serum GPx activity in AD subjects relative to healthy controls. ...
Article
Alzheimer's disease (AD) is a progressive neurodegenerative disorder first described in 1906 that is currently estimated to impact ∼40 million people worldwide. Extensive research activities have led to a wealth of information on the pathogenesis, hallmarks, and risk factors of AD; however, therapeutic options remain extremely limited. The large number of pathogenic factors that have been reported to potentially contribute to AD include copper dyshomeostasis as well as increased oxidative stress, which is related to alterations to molecular antioxidants like glutathione (GSH). While the individual roles of GSH and copper in AD have been studied by many research groups, their interactions have received relatively little attention, although they appear to interact and affect each other's regulation. Existing knowledge on how GSH-copper interactions may affect AD is sparse and lacks focus. This review first highlights the most relevant individual roles that GSH and copper play in physiology and AD, and then collects and assesses research concerning their interactions, in an effort to provide a more accessible and understandable picture of the role of GSH, copper, and their interactions in AD.
... By proteomic approaches, oxidized forms of specific proteins have been identified in CSF from AD (i.e., apolipoprotein E and alpha-1-antitrypsin among others) [4,6,7]. Similarly, in plasma from AD patients, elevated levels of protein oxidation markers have been also observed, including albumin [4,[8][9][10]. ...
... In patients with probable AD, a pathophysiologic imbalance in favor of oxidants against antioxidants has been shown in blood/plasma [8][9][10][33][34][35][36] as well as in CSF/brain [4,6,7]. Due to is closeness to the central nervous system, CSF is the most logical source to look for biomarkers directly related to AD pathology, although recognizing that its collection is invasive. ...
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Background: Oxidative stress in the brain and peripheral systems is considered a major player in Alzheimer's disease (AD). Albumin is the main transporter and the main extracellular antioxidant in the human body. Objective: Here we explore for the first time the oxidation status of cerebrospinal fluid (CSF) and plasma albumin in AD in comparison to healthy subjects. Methods: Plasma and CSF samples were obtained from mild-moderate AD patients and control healthy age-matched donors. Albumin redox state forms (reduced: HMA; reversibly oxidized: HNA1; irreversibly oxidized: HNA2) were determined by HPLC. Albumin post-translational modifications (PTM) analysis was performed by mass spectrometry. Results: HPLC showed less HMA in AD plasma than in controls (54.1% versus 65.2% ; p < 0.0001), mainly at expense of HNA1 (42.8% versus 32.5% ; p < 0.0001). In AD CSF, HMA was drastically decreased compared to controls (9.6% versus 77.4% ; p < 0.0001), while HNA2 was increased (52.8% versus 7.4% ; p < 0.0001). In AD patients but not in healthy controls, CSF albumin was much more irreversibly oxidized than in plasma (close to 20-fold increase in HNA2). PTM analysis showed that AD CSF albumin samples behave as a differentiated cluster, thus confirming the albumin oxidative pattern observed by HPLC. Conclusion: CSF albumin oxidation in AD patients was dramatically increased comparing to healthy controls, while in plasma this increase was smaller. CSF albumin in AD patients was much more oxidized than in plasma, but this effect was not observed in healthy controls. These results suggest that albumin oxidation, especially in CSF, and its role in AD deserves further investigation.
... The role of lipid peroxidation in AD development has been largely studied 10 , but few studies have been carried out determining isoprostanoids as target metabolites in AD 17,29 . In addition, the analytical methods used in most of these works were based on commercial kits or immunoassays what is associated to low specificity on isomers determinations 30 . Nevertheless, in the present study a previously validated analytical method based on mass spectrometry detection has been used, providing high selectivity and sensitivity, as well as high reliability to determine simultaneously several isoprostanoids isomers 26 . ...
Article
Neurodegenerative diseases have great social and economic impact and cause millions of deaths every year. The potential molecular mechanisms in these pathologies have been widely studied and implicate lipid peroxidation as an important factor in the development of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases. Data indicates that pathologic mechanisms specifically involve ferroptosis and mitochondrial dysfunction. Here we review the molecular mechanisms related to the lipid peroxidation that involve the development of neurodegeneration, as well as the utility of some biomarkers in diagnosis, prognosis and evaluation of new therapies for neurodegenerative diseases.
... ed at 10,000g for 5 minutes at 4 o C. Thereafter, 0.5ml of the supernatant was added to 4.5ml of Ellman's reagent. A blank was prepared with 0.5ml of the diluted precipitating agent and 4.5ml of Ellman's reagent. Reduced glutathione, GSH, is proportional to the absorbance at 412nm. For GSSG determination, 2-vinylpyridine was used to derivatize GSH (Puertas et. al., 2012). ...
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Gymnema sylvestre R.Br. ("periploca of the woods" in English; "Kafi suga" in Hausa) (Asclepiadaceae) and Combretum micranthum, Fam. (Géézà in Hausa) (Combretaceae)) are used in combination for the management of diabetes mellitus (DM) in the NorthEastern part of Nigeria with little or no scientific basis. It is thus the aim of this research to validate the anti-diabetic activities of G. sylvestre (GS) and C. micranthum (CM) leaf extracts, individually and in combined form (GSCM) as well as look at the relationship between antioxidant capacity and anti-hyperglycemic potential of these plants. The study assayed for anti-diabetic potential by following fasting blood glucose (FBG). Levels of liver catalase (CAT), malondialdehyde (MDA), superoxide dismutase (SOD), reaction oxygen species (ROS), reduced glutathione (GSH), oxidized glutathione (GSSG) and glutathione peroxidase (GSH-Px), and radical scavenging activities of the plants were assayed for spectrophotometrically. GS and CM revealed good ferric reducing antioxidant power (FRAP) and radical scavenging activities against ABTS, DPPH and Nitric Oxide with C. micranthum being significantly better-both plants also showed good total flavonoids and total phenolic contents. The anti-hyperglycemic activities may be associated with flavonoids and phenolic compounds which act via radical scavenging/antioxidant properties of the plants' extracts. In conclusion, G. sylvestre and C. micranthum aqueous leaf extracts showed significant (P < 0.05) hypoglycaemic activities both separately and in a 1:1 combination
... Some studies have confirmed that in the plasma of AD patients the quantity of 4-HNE was higher compared to the controls, indicating its role as a blood marker of lipid peroxidation [145][146][147]. Some studies have also shown that the serum or plasma levels of TBARS in AD subjects are significantly higher than in disease-free subjects [148][149][150], however, these results are still partially controversial considering that many other studies did not observe a significant difference in these levels between AD and age-matched control individuals [151,152]. ...
Article
Background Blood-based biomarkers can be very useful in formulating new diagnostic and treatment proposals in the field of dementia, especially in Alzheimer’s disease (AD). However, due to the influence of several factors on the reproducibility and reliability of these markers, their clinical use is still very uncertain. Thus, up-to-date knowledge about the main blood biomarkers that are currently being studied is extremely important in order to discover clinically useful and applicable tools, which could also be used as novel pharmacological strategies for the AD treatment. Objective The aim of this paper was to carry out a literature review on the major blood-based biomarkers for AD, connecting them with the pathophysiology of the disease. Results Recent advances in the search of blood-based AD biomarkers were summarized in this review. The biomarkers were classified according to the topics related to the main hallmarks of the disease such as inflammation, amyloid, and tau deposition, synaptic degeneration and oxidative stress. Moreover, molecules involved in the regulation of proteins related to these hallmarks were described, such as non-coding RNAs, neurotrophins, growth factors and metabolites. Cells or cellular components with potential to be considered as blood-based AD biomarkers were described in a separate topic. Conclusion A series of limitations undermine new discoveries on blood-based AD biomarkers. The lack of reproducibility of findings due to the small size and heterogeneity of the study population, different analytical methods and other assay conditions make longitudinal studies necessary in this field to validate these structures, especially when considering a clinical evaluation that includes a broad panel of these potential and promising blood-based biomarkers.
... This detoxification system requires the antioxidant glutathione (GSH) to form hemithioacetal then S-lactoylglutathione. GLO-2 catalyzes the transformation of S-lactoylglutathione into D-lactate and recycling GSH [56]. However, the decrease of circulating GSH in AD [57,58] could limit the glyoxalase activity. ...
Article
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Methylglyoxal (MG) and glyoxal (GO) are suggested to be associated with the development of neurodegenerative pathologies. However, their peripheral levels in relation to cognitive decline and their effects on key factors in neuronal cells are poorly investigated. The aim of this study was to determine their serum levels in MCI (mild cognitive impairment) and Alzheimer's disease (AD) patients, to analyze their effects on the neurotrophic and inflammatory factors, on neurodegenerative markers in neuronal cells and in neuronal derived-extracellular vesicles (nEVs). Our results show that MG and GO levels in serum, determined by HPLC, were higher in MCI. ROC (receiver-operating characteristic curves) analysis showed that the levels of MG in serum have higher sensitivity to differentiate MCI from controls but not from AD. Meanwhile, serum GO levels differentiate MCI from control and AD groups. Cells and nEVs levels of BDNF, PRGN, NSE, APP, MMP-9, ANGPTL-4, LCN2, PTX2, S100B, RAGE, Aβ peptide, pTau T181 and alpha-synuclein were quantified by luminex assay. Treatment of neuronal cells with MG or GO reduced the cellular levels of NSE, PRGN, APP, MMP-9 and ANGPTL-4 and the nEVs levels of BDNF, PRGN and LCN2. Our findings suggest that targeting MG and GO may be a promising therapeutic strategy to prevent or delay the progression of AD.
... The comprehension of the mechanisms leading to neurodegeneration and cognitive impairment is a challenging task and inflammatory mechanisms [4][5][6] and iron-driven oxidative stress are key recognised physiopathological processes. Iron is essential for neuronal life but when exceeding it might result deleterious for brain cell functions [7][8][9][10] producing reactive oxygen species (ROS) and pro-inflammatory proteins [11,12] not optimally handled in AD and MCI patients [13][14][15]. ...
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Cognitive impairments of different aetiology share alterations in iron and lipid homeostasis with mutual relationships. Since iron and cholesterol accumulation impact on neurodegenerative disease, the associated gene variants are appealing candidate targets for risk and disease progression assessment. In this light, we explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes and in the main lipoprotein transporter gene (APOE) in a cohort of 765 patients with dementia of different origin: Alzheimer's disease (AD) n = 276; vascular dementia (VaD), n = 255; mild cognitive impairment (MCI), n = 234; and in normal controls (n = 1086). In details, four genes of iron homeostasis (Hemochromatosis (HFE: C282Y, H63D), Ferroportin (FPN1: -8CG), Hepcidin (HAMP: -582AG), Transferrin (TF: P570S)), and the three major alleles of APOE (APOE2, APOE3, APOE4) were analyzed to explore causative interactions and synergies. In single analysis, HFE 282Y allele yielded a 3-fold risk reduction in the whole cohort of patients (P
... The role of lipid peroxidation in AD development has been largely studied 10 , but few studies have been carried out determining isoprostanoids as target metabolites in AD 17,29 . In addition, the analytical methods used in most of these works were based on commercial kits or immunoassays what is associated to low specificity on isomers determinations 30 . Nevertheless, in the present study a previously validated analytical method based on mass spectrometry detection has been used, providing high selectivity and sensitivity, as well as high reliability to determine simultaneously several isoprostanoids isomers 26 . ...
Article
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Alzheimer Disease (AD) standard biological diagnosis is based on expensive or invasive procedures. Recent research has focused on some molecular mechanisms involved since early AD stages, such as lipid peroxidation. Therefore, a non-invasive screening approach based on new lipid peroxidation compounds determination would be very useful. Well-defined early AD patients and healthy participants were recruited. Lipid peroxidation compounds were determined in urine using a validated analytical method based on liquid chromatography coupled to tandem mass spectrometry. Statistical studies consisted of the evaluation of two different linear (Elastic Net) and non-linear (Random Forest) regression models to discriminate between groups of participants. The regression models fitted to the data from some lipid peroxidation biomarkers (isoprostanes, neuroprostanes, prostaglandines, dihomo-isoprostanes) in urine as potential predictors of early AD. These prediction models achieved fair validated area under the receiver operating characteristics (AUC-ROCs > 0.68) and their results corroborated each other since they are based on different analytical principles. A satisfactory early screening approach, using two complementary regression models, has been obtained from urine levels of some lipid peroxidation compounds, indicating the individual probability of suffering from early AD.
... On the other hand, we determined SOD, CAT, GSH-Px activities and GSH levels to examine the antioxidant defense system. We found a significant reduction in SOD/CAT and GSH/GSH-Px system that is in accordance with the findings of some animal and human studies (Kaminsky and Kosenko, 2008;Padurariu et al., 2010;Puertas et al., 2012). However, other studies in the literature reported contradictory findings such as no change in GSH-Px (Marcus et al., 1998;Sultana et al., 2008), a significant increase (Lovell et al., 1995)or no change (Gsell et al., 1995) in SOD or increased CAT activity (Lovell et al., 1995) in AD. ...
Article
In the present study, we examined whether rosmarinic acid (RA) reverses amyloid β (Aβ) induced reductions in antioxidant defense, lipid peroxidation, cholinergic damage as well as the central auditory deficits. For this purpose, Wistar rats were randomly divided into four groups; Sham(S), Sham + RA (SR), Aβ42 peptide (Aβ) and Aβ42 peptide + RA (AβR) groups. Rat model of Alzheimer was established by bilateral injection of Aβ42 peptide (2,2 nmol/10 μl) into the lateral ventricles. RA (50 mg/kg, daily) was administered orally by gavage for 14 days after intracerebroventricular injection. At the end of the experimental period, we recorded the auditory event related potentials (AERPs) and mismatch negativity (MMN) response to assess auditory functions followed by histological and biochemical analysis. Aβ42 injection led to a significant increase in the levels of thiobarbituric acid reactive substances (TBARS) and 4-Hydroxy-2-nonenal (4-HNE) but decreased the activity of antioxidant enzymes (SOD, CAT, GSH-Px) and glutathione levels. Moreover, Aβ42 injection resulted in a reduction in the acetylcholine content and acetylcholine esterase activity. RA treatment prevented the observed alterations in the AβR group. Furthermore, RA attenuated the increased Aβ staining and astrocyte activation. We also found that Aβ42 injection decreased the MMN response and theta power/coherence of AERPs, suggesting an impairing effect on auditory discrimination and echoic memory processes. RA treatment reversed the Aβ42 related alterations in AERP parameters. In conclusion, our study demonstrates that RA prevented Aβ-induced antioxidant-oxidant imbalance and cholinergic damage, which may contribute to the improvement of neural network dynamics of auditory processes in this rat model.
... Nevertheless, both establishing the right pattern of redox markers to analyze as well as choosing the most appropriate sample type remain a challenge in AD. Most of the studies have been focused on the search for redox markers in plasma or serum [19,20]. However, the redox status of erythrocytes is essential for adequate oxygen delivery to the whole body. ...
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Oxidative stress plays an essential and early role in the pathophysiology of Alzheimer's disease (AD). Alterations in the redox state in AD and in mild cognitive impairment (MCI) patients appear in the brain and at peripheral level. Given that it is easier to study the latter, most of the research has been focused on plasma. However, the analysis of redox parameters in whole blood cells (including erythrocytes and leukocytes) has not really been investigated. Moreover, the association of these parameters with Mini-Mental State Examination (MMSE) clinical scores, has scarcely been studied. Therefore, the aim of the present work was to analyze several redox markers in whole blood cells from male and female MCI and AD patients. Antioxidant (superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx), and reductase (GR) activities, and reduced glutathione (GSH) concentration) together with oxidant parameters (oxidized glutathione (GSSG) and thiobarbituric acid-reactive substances (TBARS)) were investigated using MCI and AD (10 women and 10 men in each group) and their age-matched control groups (15 women and 15 men). The results show an altered redox state in whole blood cells from AD patients (higher CAT, GSSG/GSH, TBARS and lower GPx, GR, GSH). Some of these redox parameters are already affected in MCI patients (higher TBARS and lower GPx and GR activities) in both sexes and, consequently, they could be used as markers of prodromal AD. Since GR, GSH, GSSG, and GSSG/GSH were found to be associated with MMSE scores, they seem to be useful clinically to monitor cognitive decline in AD progression.
... Markers of oxidative stress can be useful for diagnosing AD at the earliest stages of disease. Oxidative stress damage occurs in MCI and AD patients, who exhibit diminished antioxidant defenses and elevated levels of oxidative damage markers (Nunomura et al., 2001;Puertas et al., 2012); these are also observed early in AD development in the 3×Tg-AD mouse model and have been linked to Aβ-induced neurotoxicity (Resende et al., 2008;Torres-Lista et al., 2014). Brain homogenates prepared from the cerebral cortex of female 3×Tg-AD mice show evidence of oxidative stress (Resende et al., 2008) and oxidative status in neurons and glia in the cerebellum, hippocampus, and cerebral cortex is correlated with oxidative stress of peripheral leukocytes in mice displaying anxiety (Rammal et al., 2008). ...
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Structural and functional abnormalities in the cerebral microvasculature have been observed in Alzheimer's disease (AD) patients and animal models. One cause of hypoperfusion is the thickening of the cerebrovascular basement membrane (CVBM) due to increased collagen-IV deposition around capillaries. This study investigated whether these and other alterations in the cerebrovascular system associated with AD can be prevented by long-term dietary supplementation with the antioxidant ubiquinol (Ub) stabilized with Kaneka QH P30 powder containing ascorbic acid (ASC) in a mouse model of advanced AD (3 × Tg-AD mice, 12 months old). Animals were treated from prodromal stages of disease (3 months of age) with standard chow without or with Ub + ASC or ASC-containing vehicle and compared to wild-type (WT) mice. The number of β-amyloid (Aβ) plaques in the hippocampus and entorhinal cortex was higher in female than in male 3 × Tg-AD mice. Extensive regions of hypoxia were characterized by a higher plaque burden in females only. This was abolished by Ub + ASC and, to a lesser extent, by ASC treatment. Irrespective of Aβ burden, increased collagen-IV deposition in the CVBM was observed in both male and female 3 × Tg-AD mice relative to WT animals; this was also abrogated in Ub + ASC- and ASC-treated mice. The chronic inflammation in the hippocampus and oxidative stress in peripheral leukocytes of 3 × Tg-AD mice were likewise reversed by antioxidant treatment. These results provide strong evidence that long-term antioxidant treatment can mitigate plasma oxidative stress, amyloid burden, and hypoxia in the AD brain parenchyma.
... The elevation of CML in early AD observed in this study could be related to the alteration of the antioxidant/oxidant homeostasis and to oxidative damage recently observed in the same group of patients, with an early decrease of the total antioxidant capacity in MCI and an increase of the protein carbonyls observed in early AD [56]. Similarly, several previous studies have also demonstrated that oxidative-induced damages increased early in AD [57][58][59][60][61][62][63]. In addition, CML is also a RAGE receptor ligand. ...
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Background: Both advanced glycation end products (AGEs) N-(1-carboxymethyl)-L-lysine (CML) and pentosidine were found in the brain from Alzheimer's disease (AD) patients and were associated with the neuropathological hallmarks of AD. In AD patients, the circulating level of both AGEs remains unknown. Moreover, their levels in peripheral extracellular vesicles (EVs) and their association with AD remain to be determined. Finally, it is not known if neuronal cells can release AGEs via EVs and propagate AGEs. Objective: To determine the levels of circulating CML and pentosidine during the progression of AD. Moreover, their levels in circulating EVs were determined and their association with the clinical cognitive scores were analyzed. Finally, we have studied the possibility that neuronal cells eliminate and transfer these AGEs through EVs. Methods: CML and pentosidine levels were measured in serum and in circulating EVs. Released-EVs from SK-N-SH neuronal cells were isolated and CML levels were also determined. Results: The levels of CML in albumin-free serum proteins were higher in the early stage of AD while the levels of pentosidine remained unchanged. In contrast, the levels of CML in the EVs were lower in the moderate stage of AD. Interestingly, the levels of CML in serum were negatively correlated with the clinical cognitive scores MMSE and MoCA. For the first time, we were able to demonstrate that CML was present in EVs released from neuronal cells in culture. Conclusion: Peripheral and circulating EVs levels of CML can differentiate early to moderate AD. In the brain, neuronal CML can propagate from cells-to-cells via EVs.
... In particular, SOD levels, but not the activity [114], were found to be elevated in the hippocampus and amygdala of AD patients [115], while a decrease in SOD, GPx, and CAT levels was found in the frontal and temporal cortex [116]. Nevertheless, CAT activity was found to increase in AD erythrocytes [117], suggesting an independence of the redox status between the periphery and the brain. ...
Article
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Age is the main risk factor for a number of human diseases, including neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, which increasing numbers of elderly individuals suffer. These pathological conditions are characterized by progressive loss of neuron cells, compromised motor or cognitive functions, and accumulation of abnormally aggregated proteins. Mitochondrial dysfunction is one of the main features of the aging process, particularly in organs requiring a high-energy source such as the heart, muscles, brain, or liver. Neurons rely almost exclusively on the mitochondria, which produce the energy required for most of the cellular processes, including synaptic plasticity and neurotransmitter synthesis. The brain is particularly vulnerable to oxidative stress and damage, because of its high oxygen consumption, low antioxidant defenses, and high content of polyunsaturated fats very prone to be oxidized. Thus, it is not surprising the importance of protecting systems, including antioxidant defenses, to maintain neuronal integrity and survival. Here, we review the role of mitochondrial oxidative stress in the aging process, with a specific focus on neurodegenerative diseases. Understanding the molecular mechanisms involving mitochondria and oxidative stress in the aging and neurodegeneration may help to identify new strategies for improving the health and extending lifespan.
... Inmunoblots were analyzed by ImageLab TM Software version 2.0.1 (Bio-Rad) to provide quantitative values for relative expression of each protein (all normalized to its own loading control). The optical densities of the bands were measured by ImageLab [29]. ...
Article
Background: Brain tumorigenesis is related to oxidative stress and a decreased response of antioxidant defense systems. Due to it is well known that gender differences exists in the incidence and survival rates of brain tumors, it is important to recognize and understand the ways in which their biology can differ. Objective: To analyze gender differences in redox status in animals with chemically-induced brain tumors. Methods: Oxidative stress parameters, non-enzyme and enzyme antioxidant defense systems are assayed in animals with brain tumors induced by transplacental N-ethyl-N-nitrosourea (ENU) administration. Both tissue and plasma were analyzed to know if key changes in redox imbalance involved in brain tumor development were reflected systemically and could be used as biomarkers of the disease. Results: Several oxidative stress parameters were modified in tumor tissue of male and female animals, changes that were not reflected at plasma level. Regarding antioxidant defense system, only glutathione (GSH) levels were decreased in both brain tumor tissue and plasma. Superoxide dismutase (SOD) and catalase (CAT) activities were decreased in brain tumor tissue of male and female animals, but plasma levels were only altered in male animals. However, different protein and mRNA expression patterns were found for both enzymes. On the contrary, glutathione peroxidase (GPx) activity showed increased levels in brain tumor tissue without gender differences, being protein and gene expression also increased in both males and female animals. However, these changes in GPx were not reflected at plasma level. Conclusion: We conclude that brain tumorigenesis was related to oxidative stress and changes in brain enzyme and non-enzyme antioxidant defense systems with gender differences, whereas plasma did not reflect the main redox changes that occur at brain level.
... In turn, Gu et al. [84], and Venkateshappa et al. [85] reported the decreased concentration of GSH in the brains of AD patients. Interestingly, also the reduced level of plasma GSH may be observed in the early stage of dementia (MCI) [86,87], and in AD patients, in whom the GSH concentration is reduced by roughly 13% [88], what is in line with our results. The reduced content of GSH is probably an effect of excessive Hcy production due to disturbed transformation to Cys [89]. ...
Article
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Alzheimer’s disease (AD) is a progressive disease, with frequently observed improper biothiols turnover, homocysteine (Hcy) and glutathione (GSH). GSH protects cells from oxidative stress and may be determined by 8-oxo-2’-deoxyguanosine (8-oxo2dG) level and its repair enzyme 8-oxoguanine DNA glycosylase (OGG1). The presence of unfavorable alleles, e.g., in APOE cluster, TOMM40 or APOC1 is known to facilitate the dementia onset under oxidative stress. The aim of the study was to analyze rs1052452, rs2075650 TOMM40 polymorphisms, rs4420638 APOC1, and their correlation with Hcy, GSH, 8-oxo2dG, OGG1 levels in plasma of AD patients and controls. We recruited 230 individuals: 88 AD, 80 controls without (UC), 62 controls with (RC) positive family history of AD. The TOMM40 genotype was determined by HRM and capillary electrophoresis, while APOC1 by HRM. The concentrations of OGG1, 8-oxo2dG were determined by ELISA, whereas Hcy, GSH by HPLC/EC. We showed that over 60% of AD patients had increased Hcy levels (p<0.01 vs. UC, p<0.001 vs. RC), while GSH (p<0.01 vs. UC), 8-oxo2dG (p<0.01 vs. UC, p<0.001 vs. RC) were reduced. Minor variants: rs10524523-L, rs4420638-G, rs2075650-G were significantly overrepresented in AD. For rs4420638-G, rs2075650-G variants, the association remained significant in APOE E4 non-carriers. The misbalance of analyzed biothiols, and 8-oxo2dG, OGG1 were more pronounced in carriers of major variants: rs10524523-S/VL, rs4420638-A, rs2075650-A. We showed, for the first time, that APOC1 and TOMM40 rs2075650 polymorphisms may be independent risk factors of developing AD, whose major variants are accompanied by disruption of biothiols metabolism and inefficient removal of DNA oxidation.
... The role of lipid peroxidation in AD development has been largely studied 10 , but few studies have been carried out determining isoprostanoids as target metabolites in AD 17,29 . In addition, the analytical methods used in most of these works were based on commercial kits or immunoassays what is associated to low specificity on isomers determinations 30 . Nevertheless, in the present study a previously validated analytical method based on mass spectrometry detection has been used, providing high selectivity and sensitivity, as well as high reliability to determine simultaneously several isoprostanoids isomers 26 . ...
Article
Background: Alzheimer's disease (AD), the most common cause of dementia in adulthood, has a great medical, social, and economic impact worldwide. Available treatments result in symptomatic relief, and most of them are indicated from early stages of the disease. Therefore, there is an increasing body of research developing accurate and early diagnoses, as well as disease-modifying therapies. Objective: Advancing the knowledge of AD physiopathological mechanisms, imporoving early diagnosis and developing effective treatments from omics-based biomarkers. Methods: Studies using omics technologies to detect early AD, were reviewed with particular focus on the metabolites/lipids, micro-RNAs and proteins, which are identified as potential biomarkers in non-invasive samples. Results: This review summarizes recent research on metabolomics/lipidomics, epigenomics and proteomics, applied to early AD detection. Main research lines are the study of metabolites from pathways, such as, lipid, amino acid and neurotransmitter metabolisms, cholesterol biosynthesis, and Krebs and urea cycles. In addition, some microRNAs and proteins (microglobulins, interleukins), related to a common network with amyloid precursor protein and tau, have been also identified as potential biomarkers. Nevertheless, the reproducibility of results among studies is not good enough and a standard methodological approach is needed in order to obtain accurate information. Conclusion: The assessment of metabolomic/lipidomic, epigenomic and proteomic changes associated with AD to identify early biomarkers in non-invasive samples from well-defined participants groups will potentially allow the advancement in the early diagnosis and improvement of therapeutic interventions.
... Endogenous antioxidant enzymes lower their activity and efficiency with age. Results from recent studies support the beneficial effect of astaxanthin on activation of antioxidant mechanisms, increasing the levels or stimulating the activity of endogenous enzymes, such as superoxide dismutase (SOD) and catalase [26,99]. A recent study [27] investigated in mice the effect of astaxanthin on antioxidant enzymes expressed in major brain structures. ...
Article
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Astaxanthin is a carotenoid with powerful antioxidant and anti-inflammatory activity produced by several freshwater and marine microorganisms, including bacteria, yeast, fungi, and microalgae. Due to its deep red-orange color it confers a reddish hue to the flesh of salmon, shrimps, lobsters, and crayfish that feed on astaxanthin-producing organisms, which helps protect their immune system and increase their fertility. From the nutritional point of view, astaxanthin is considered one of the strongest antioxidants in nature, due to its high scavenging potential of free radicals in the human body. Recently, astaxanthin is also receiving attention for its effect on the prevention or co-treatment of neurological pathologies, including Alzheimer and Parkinson diseases. In this review, we focus on the neuroprotective properties of astaxanthin and explore the underlying mechanisms to counteract neurological diseases, mainly based on its capability to cross the blood-brain barrier and its oxidative, anti-inflammatory, and anti-apoptotic properties.
... In AD patients, the dramatic increase in ROS production is accompanied by a reduction in the antioxidant enzyme systems [186][187][188][189]. For instance, the activities of SOD, CAT and GPX have been described to be significantly low in early AD [190,191]; in particular, SOD activity seems to be significantly reduced in both the extracellular and intracellular blood compartments [192,193], and SOD deficiency has been related to the increased deposition of Aβ and memory impairments, both alleviated by SOD-2 overexpression [194]. Accordingly, Fracassi and colleagues show the reduction in SOD-2 level in AD brains, especially in neuronal cells [195]. ...
Article
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Reactive oxygen species (ROS) are versatile molecules that, even if produced in the background of many biological processes and responses, possess pleiotropic roles categorized in two interactive yet opposite domains. In particular, ROS can either function as signaling molecules that shape physiological cell functions, or act as deleterious end products of unbalanced redox reactions. Indeed, cellular redox status needs to be tightly regulated to ensure proper cellular functioning, and either excessive ROS accumulation or the dysfunction of antioxidant systems can perturb the redox homeostasis, leading to supraphysiological concentrations of ROS and potentially harmful outcomes. Therefore, whether ROS would act as signaling molecules or as detrimental factors strictly relies on a dynamic equilibrium between free radical production and scavenging resources. Of notice, the mammalian brain is particularly vulnerable to ROS-mediated toxicity, because it possesses relatively poor antioxidant defenses to cope with the redox burden imposed by the elevated oxygen consumption rate and metabolic activity. Many features of neurodegenerative diseases can in fact be traced back to causes of oxidative stress, which may influence both the onset and progression of brain demise. This review focuses on the description of the dual roles of ROS as double-edge sword in both physiological and pathological settings, with reference to Alzheimer’s and Parkinson’s diseases.
... Markers of oxidative stress can be useful for diagnosing AD in the earliest stages of the disease. Some studies have shown that oxidative stress damage occurs in mild cognitive impairment and AD patients who exhibit diminished antioxidant defenses and higher levels of oxidative damage markers (Padurariu et al. 2010;Puertas et al. 2012). However, the published data about serum CoQ concentration obtained from AD patient are conflicting. ...
Chapter
Parkinson’s Disease (PD) and Alzheimer’s Disease (AD) are the two most common neurodegenerative diseases in the elderly. Both are proteinopathies that interact with mitochondria, which generate reactive oxygen species (ROS) and leads to mitochondria-activated programmed neuronal death. Several lines of evidence suggest that oxidative stress and mitochondrial dysfunction play central roles in the onset and progression of both diseases. Redox status of coenzyme Q10 (CoQ) in the plasma or cerebrospinal fluid are altered in PD and AD patients; as such, neuroprotective strategies targeting mitochondria such as the use of a supplement containing CoQ have been proposed as treatment. Preclinal data in cellular and animal models have yielded promising results, including the protection of mitochondria from biochemical insults and inhibition of α-synuclein aggregation in dopaminergic neurons in PD models and a reduction of Aβ burden in the cortex and hippocampus in an AD model. However, CoQ failed to elicit therapeutic effects in humans, likely because patients received treatment at late stages, indicating that the complexities of human disease cannot be fully recapitulated by animal models.
... Meanwhile, extensive experiments collectively verify that antioxidants do delay the occurrence and progression of AD [48]. These oxidative stress indicators are used to characterize the earliest events of AD and are reliable tools for early diagnosis and prevention of AD [49]. ...
Article
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Neurological function deficits due to cerebral ischemia or neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) have long been considered a thorny issue in clinical treatment. Recovery after neurologic impairment is fairly limited, which poses a major threat to health and quality of life. Accumulating evidences support that ROS and autophagy are both implicated in the onset and development of neurological disorders. Notably, oxidative stress triggered by excess of ROS not only puts the brain in a vulnerable state but also enhances the virulence of other pathogenic factors, just like mitochondrial dysfunction, which is described as the culprit of nerve cell damage. Nevertheless, autophagy is proposed as a subtle cellular defense mode against destructive stimulus by timely removal of damaged and cytotoxic substance. Emerging evidence suggests that the interplay of ROS and autophagy may establish a determinant role in the modulation of neuronal homeostasis. However, the underlying regulatory mechanisms are still largely unexplored. This review sets out to afford an overview of the crosstalk between ROS and autophagy and discusses relevant molecular mechanisms in cerebral ischemia, AD, and PD, so as to provide new insights into promising therapeutic targets for the abovementioned neurological conditions.
... The dysfunction of such proteins is likely related to the pathology of AD [111]. Consistently, high levels of protein oxidation markers have been observed in plasma from AD patients including albumin [111][112][113][114]. ...
Article
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Alzheimer’s disease (AD) is a neurodegenerative process that inexorably leads to progressive deterioration of cognition function and, ultimately, death. Central pathophysiologic features of AD include the accumulation of extracellular plaques comprised of amyloid-β peptide (Aβ) and the presence of intraneuronal neurofibrillary tangles. However, a large body of evidence suggests that oxidative stress and inflammation are major contributors to the pathogenesis and progression of AD. To date, available pharmacologic treatments are only symptomatic. Clinical trials focused on amyloid and non-amyloid-targeted treatments with small molecule pharmacotherapy and immunotherapies have accumulated a long list of failures. Considering that around 90% of the circulating Aβ is bound to albumin, and that a dynamic equilibrium exists between peripheral and central Aβ, plasma exchange with albumin replacement has emerged as a new approach in a multitargeted AD therapeutic strategy (AMBAR Program). In plasma exchange, a patient’s plasma is removed by plasmapheresis to eliminate toxic endogenous substances, including Aβ and functionally impaired albumin. The fluid replacement used is therapeutic albumin, which acts not only as a plasma volume expander but also has numerous pleiotropic functions (e.g., circulating Aβ- binding capacity, transporter, detoxifier, antioxidant) that are clinically relevant for the treatment of AD. Positive results from the AMBAR Program (phase 1, 2, an 2b/3 trials), i.e., slower decline or stabilization of disease symptoms in the most relevant clinical efficacy and safety endpoints, offer a glimmer of hope to both AD patients and caregivers.
... There have been many studies that reported a connection between oxidative stress and the development of several diseases. It is usually noted that the degree of plasma oxidation increases with aging and not much differs by gender [15][16][17][18][19] . In the presented study, no significant correlations between age and markers of oxidative stress were observed (Table 1; correlation coefficient r ranging from 0.02 to 0.25; p > 0.05). ...
Article
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The aim of this study was to examine the usefulness of time-resolved fluorescence spectroscopy in the evaluation of the oxidative processes in human plasma. To investigate the impact of oxidative stress on the fluorescence of plasma, five studied markers (thiobarbituric acid-reactive substances, ischemia modified albumin, carbonyl groups, hydrogen peroxide, advanced oxidation protein products) were chosen as oxidative damage approved markers. Our method presents several advantages over traditional methods as it is a direct, non-time-consuming, repeatable, and non-invasive technique that requires only simple pre-treatment of samples without additional reagents and the sample size needed for analysis is small. In principle, each modification of the protein in plasma can be expected to modify its fluorescence properties and hence its lifetime or intensity. The study involved 59 blood donors with no evidence of disease. The research was conducted at excitation wavelengths of 280 nm and 360 nm, and emission was measured at wavelengths of 350 nm and 440 nm, respectively. Our results, although preliminary, suggest that the application of fluorescence measurements can be considered as an effective marker of oxidative stress. Regression analyses showed that a notable growth in fluorescence intensity at 440 nm and a simultaneous decrease in fluorescence intensity and mean fluorescence lifetime at 350 nm are associated with higher levels of oxidative stress.
... It is well documented that AD patients encounter extensive oxidative stress in the brain and peripheral tissues (Puertas et al. 2012;Huang et al. 2016). Physiopathologically, oxidative stress is the state of imbalance between antioxidants and oxidants (Chang et al. 2014;Hemmati-Dinarvand et al. 2017). ...
Article
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Early diagnosis of Alzheimer's Disease (AD) using potential biomarkers may help with implementing early therapeutic interventions, monitoring, and ultimately disease treatment. The current study aimed to evaluate serum levels of DKK-1, TNC, and oxidative stress markers, as well as analyzing the expression of LRP6, GSK3A, GSK3B genes in patients with AD. Serum levels of DKK-1, TNC, TOS, TAC, and MDA were measured in 40 AD patients and 40 healthy individuals. Additionally, the relative expressions of LRP6, GSK3A, and GSK3B genes in whole blood were evaluated. Receiver operating characteristic (ROC) analysis was used to investigate the incremental diagnostic value of each factor in the study groups. Mean serum levels of DKK-1, TNC, TOS, TAC, and MDA were significantly higher in the AD group compared to the healthy group (p<0.001). Moreover, a significant difference was observed in the expression of LRP6 and GSK3A genes (p<0.001) between patients and healthy groups. However, the expression of GSK3B did not significantly differ between the two groups (P>0.05). With considerable sensitivity and specificity, ROC analysis demonstrated the diagnostic efficacy of DKK-1 and TNC serum levels in AD within an area under the ROC curve of ≥ 0.98 (p˂0.001). The results showed that evaluating serum levels of DKK-1 and TNC, as well as assessing the expression of LRP6, could be utilized for diagnosis and monitoring of AD patients.
... In addition, reductions in glutathione level, and catalase and superoxide dismutase activities are commonly used as markers of oxidative stress [43][44][45]. Sleep deprivation has been established to induce reduced antioxidant levels in different brain regions [16,46] and this conforms to our findings which revealed reduced serum glutathione level and catalase and SOD activities following paradoxical sleep deprivation which may be due to increased free radical production triggered by PSD. However, DRLC treatment in this study was associated with an increased antioxidant level characterized by elevated GSH levels as well as increased catalase and SOD activities. ...
... Several studies have explored the potential role of plasma GSH as a biomarker that reflects the systemic redox status for AD or mild cognitive impairment (MCI), but their findings are controversial. Some of these studies have found that individuals with AD or MCI have lower levels of plasma GSH compared to healthy controls [16][17][18][19][20][21][22][23], while others have not reported such findings [24][25][26][27][28][29][30][31]. There is also evidence that higher plasma GSH is associated with better performance on cognitive screening tests (such as the mini mental state examination-MMSE) and less impairment on cognitive performance overall [17,18,20,31,32]. ...
Article
Background Potential links between oxidative stress and the pathophysiology of Alzheimer's disease (AD) have been reported in the existing literature. Biological markers of oxidative stress, such as the reduced form of glutathione (GSH), may have a potential role as predictive biomarkers for AD development. The aim of the present study was to explore the longitudinal associations between plasma GSH and the risk of developing AD or cognitive decline, in a sample of community-dwelling, non-demented older adults. Methods Participants from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) were included in the present prospective study. The sample used in the analyses consisted of 391 non-demented individuals over the age of 64 (mean age = 73.85 years; SD = 5.06), with available baseline GSH measurements and longitudinal follow-up. Plasma GSH was treated both as a continuous variable and as tertiles in our analyses. Cox proportional hazards models were used to evaluate the hazard ratio (HR) for AD incidence as a function of baseline plasma GSH. Generalized estimating equations (GEE) models were deployed to explore the associations between baseline plasma GSH and the rate of change of performance scores on individual cognitive domains over time. Models were adjusted for age, years of education and sex. Supplementary exploratory models were also adjusted for mild cognitive impairment (MCI) at baseline, risk for malnutrition, physical activity and adherence to the Mediterranean dietary pattern. Results A total of 24 incident AD cases occurred during a mean (SD) of 2.99 (0.92) years of follow-up. Individuals in the highest GSH tertile group (highest baseline plasma GSH values) had a 70.1% lower risk for development of AD, compared to those in the lowest one [HR = 0.299 (0.093–0.959); p = 0.042], and also demonstrated a slower rate of decline of their executive functioning over time (5.2% of a standard deviation less decline in the executive composite score for each additional year of follow-up; p = 0.028). The test for trend was also significant suggesting a potential dose-response relationship. Conclusion In the present study, higher baseline plasma GSH levels were associated with a decreased risk of developing AD and with a better preservation of executive functioning longitudinally.
... There is a causal relationship between GSH metabolism and diseases such as cancer, neurodegenerative diseases, cystic fibrosis, human immunodeficiency diseases and aging (Seshadri et al. 2002). GSH levels in patients with AIDS and Alzheimer's disease are low (Borges-Santos et al. 2012;Puertas et al. 2012), and GSH levels in patients with neurodegenerative diseases are on the rise (Baillet et al. 2010). The imbalance of GSH synthesis is the cause of many pathological conditions, including diabetes, pulmonary fibrosis, and endotoxemia (Townsend et al. 2003;Lu 2009). ...
Article
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Biothiols play important roles in various physiological and biological processes, which closely related to many diseases. Hydrazine is widely used in the chemical industry, but it is harmful to humans and animals. Therefore, it is very important to develop a fluorescent probe that can simultaneously detect biological thiols and hydrazine. In this work, a new fluorescent probe (2E,4Z)-2-(benzo[d]thiazol-2-yl)-5-chloro-5-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)penta-2,4-dienenitrile (BCD) was synthesized by integrating coumarin and benzothiazole acetonitrile. Featured with four binding sites and different bonding mechanism between probe with biothiols and hydrazine, this probe exhibited fluorescent turn-on for distinguishing Cys, Hcy, GSH and hydrazine with 760-, 8-, 6- and 637-fold fluorescent intensity increase at 502, 479, 476 and 458 nm, respectively, through different excitation wavelengths. Research on the effect of pH on the fluorescent performance of BCD shows that the probe exhibits superior stability in a weakly alkaline to weakly acidic environment, which will facilitate the detection of biological thiols or hydrazine hydrate by BCD. Selectivity studies have shown that the probe has high specificity to biological thiols and hydrazine, which is of great significance to the application of BCD.
... Hyperphosphorylated forms of TAU often contribute to increased development of reactive oxygen (ROS) species and decreased detoxifying enzyme activity, including superoxide dismutase (6). Superoxide dismutase (SOD) is associated with vascular/neuro-inflammation control (7). Research on predictors of dementia factors in Indonesia is still limited. ...
Article
Accumulation of phosphorylated-tau and low levels of superoxide dismutase is associated with dementia affecting the quality of life in the elderly. This study aimed to determine differences in quality of life (QoL), phosphorylated-tau (p-TAU), and superoxide dismutase (SOD) plasma in women elderly with and without dementia. The research method was a cross-sectional study. Examination of dementia using MMSE (Mini-Mental State Examination) and CDR (Clinical Dementia Rating Scale). The measure of the quality of life using the WHO-QoL questionnaire and plasma level of p-TAU and SOD using ELISA (Enzyme-linked Immunosorbent Assay). The research sample consisted of 70 women elderly mean aged 74.69 ± 9.27 years who lived in three nursing homes. Data analysis used fisher test, independent sample t-test, Mann-Whitney test, and linear regression test. The findings showed that the quality of life differed significantly in the domain of physic (p=0.001), social-relationship (p=0.002), psychological (p<0.001), environment (p<0.001), and plasma level of p-TAU (p=0.028) and SOD (p<0.001) in women elderly with and without dementia. In term of its association with dementia, p-TAU (p=0.001), SOD (p=0.003), MMSE (p=0.028), and QoL-social (p=0.176) were final model factors of dementia in women elderly. In conclusion, there are significant differences in quality of life, p-TAU, and plasma SOD between women elderly with and without dementia.
... Non-enzymatic reactions were important for the evolution of metabolic pathways but are retained as part of the modern metabolic network. They divide into unspecific chemical reactivity and specific reactions that occur either exclusively nonenzymatically as part of the metabolic network, or in parallel to existing enzyme functions [1][2][3][4]. ...
... Astaxanthin may elevate the levels of intracellular antioxidant enzymes including catalase and SOD. This improves cognitive function in neurodegeneration as well as in ageing, as these antioxidant molecules decreases with age (Haider et al., 2014;Puertas et al., 2012). SOD, catalase and other antioxidants are mainly involved in protection of brain tissues from ROS damage. ...
Article
Background Despite advances in research on neurodegenerative diseases, the pathogenesis and treatment response of neurodegenerative diseases remain unclear. Recent studies revealed a significant role of carotenoids to treat neurodegenerative diseases. The aim of this study was to systematically review the neuroprotective potential of carotenoids in vivo and in vitro and the molecular mechanisms and pathological factors contributing to major neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and stroke). Hypothesis Carotenoids as therapeutic molecules to target neurodegenerative diseases. Results Aggregation of toxic proteins, mitochondrial dysfunction, oxidative stress, the excitotoxic pathway, and neuroinflammation were the major pathological factors contributing to the progression of neurodegenerative diseases. Furthermore, in vitro and in vivo studies supported the beneficiary role of carotenoids, namely lycopene, β-carotene, crocin, crocetin, lutein, fucoxanthin and astaxanthin in alleviating disease progression. These carotenoids provide neuroprotection by inhibition of neuro-inflammation, microglial activation, excitotoxic pathway, modulation of autophagy, attenuation of oxidative damage and activation of defensive antioxidant enzymes. Additionally, studies conducted on humans also demonstrated that dietary intake of carotenoids lowers the risk of neurodegenerative diseases. Conclusion Carotenoids may be used as drugs to prevent and treat neurodegenerative diseases. Although, the in vitro and in vivo results are encouraging, further well conducted clinical studies on humans are required to conclude about the full potential of neurodegenerative diseases.
... The administration of exogenous antioxidants is beneficial in treating the side effects of OS by compensating the inefficacy of the endogenous defense systems through inhibiting the intricate network of oxidative damage pathways and enhancing the systemic antioxidant response [20]. AST acts through exogenous antioxidant mechanisms as well as stimulating endogenous anti-oxidative enzymes [148,149,153], which is of importance given that, with age, the concentration of endogenous antioxidant enzymes decreases along with the efficiency and activity of these enzymes. Previous studies have shown that oral supplementation of SOD was found to promote the circulation, in blood and brain, of endogenous enzymes such as SOD and CAT [154]. ...
Article
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Oxidative stress, the imbalance of the antioxidant system, results in an accumulation of neurotoxic proteins in Alzheimer's disease (AD). The antioxidant system is composed of exogenous and endogenous antioxidants to maintain homeostasis. Superoxide dismutase (SOD) is an endogenous enzymatic antioxidant that converts superoxide ions to hydrogen peroxide in cells. SOD supplementation in mice prevented cognitive decline in stress-induced cells by reducing lipid peroxidation and maintaining neurogenesis in the hippocampus. Furthermore, SOD decreased expression of BACE1 while reducing plaque burden in the brain. Additionally, Astaxanthin (AST), a potent exogenous carotenoid, scavenges superoxide anion radicals. Mice treated with AST showed slower memory decline and decreased depositions of amyloid-beta (A β ) and tau protein. Currently, the neuroprotective potential of these supplements has only been examined separately in studies. However, a single antioxidant cannot sufficiently resist oxidative damage to the brain, therefore, a combinatory approach is proposed as a relevant therapy for ameliorating pathological changes in AD.
Article
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Background: Increasing evidence implicates oxidative stress (OS) in Alzheimer disease (AD) and mild cognitive impairment (MCI). Depletion of the brain antioxidant glutathione (GSH) may be important in OS-mediated neurodegeneration, though studies of post-mortem brain GSH changes in AD have been inconclusive. Recent in vivo measurements of the brain and blood GSH may shed light on GSH changes earlier in the disease. Aim: To quantitatively review in vivo GSH in AD and MCI compared to healthy controls (HC) using meta-analyses. Method: Studies with in vivo brain or blood GSH levels in MCI or AD with a HC group were identified using MEDLINE, PsychInfo, and Embase (1947-June 2020). Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes using random effects models. Outcome measures included brain GSH (Meshcher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) versus non-MEGA-PRESS) and blood GSH (intracellular versus extracellular) in AD and MCI. The Q statistic and Egger's test were used to assess heterogeneity and risk of publication bias, respectively. Results: For brain GSH, 4 AD (AD=135, HC=223) and 4 MCI (MCI=213, HC=211) studies were included. For blood GSH, 26 AD (AD=1203, HC=1135) and 7 MCI (MCI=434, HC=408) studies were included. Brain GSH overall did not differ in AD or MCI compared to HC; however, the subgroup of studies using MEGA-PRESS reported lower brain GSH in AD (SMD [95%CI] -1.45 [-1.83, -1.06], p<0.001) and MCI (-1.15 [-1.71, -0.59], z=4.0, p<0.001). AD had lower intracellular and extracellular blood GSH overall (-0.87 [-1. 30, -0.44], z=3.96, p<0.001). In a subgroup analysis, intracellular GSH was lower in MCI (-0.66 [-1.11, -0.21], p=0.025). Heterogeneity was observed throughout (I2 >85%) and not fully accounted by subgroup analysis. Egger's test indicated risk of publication bias. Conclusion: Blood intracellular GSH decrease is seen in MCI, while both intra- and extracellular decreases were seen in AD. Brain GSH is decreased in AD and MCI in subgroup analysis. Potential bias and heterogeneity suggest the need for measurement standardization and additional studies to explore sources of heterogeneity.
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Current research efforts on neurological diseases are focused on identifying novel disease biomarkers to aid in diagnosis, provide accurate prognostic information and monitor disease progression. With advances in detection and quantification methods in genomics, proteomics and metabolomics, saliva has emerged as a good source of samples for detection of disease biomarkers. Obtaining a sample of saliva offers multiple advantages over the currently tested biological fluids as it is a non-invasive, painless and simple procedure that does not require expert training or harbour undesirable side effects for the patients. Here, we review the existing literature on salivary biomarkers and examine their validity in diagnosing and monitoring neurodegenerative and neuropsychiatric disorders such as autism and Alzheimer's, Parkinson's and Huntington's disease. Based on the available research, amyloid beta peptide, tau protein, lactoferrin, alpha-synuclein, DJ-1 protein, chromogranin A, huntingtin protein, DNA methylation disruptions, and micro-RNA profiles provide display a reliable degree of consistency and validity as disease biomarkers.
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Background: Increasing evidence implicates oxidative stress (OS) in Alzheimer Disease (AD) and Mild Cognitive Impairment (MCI). Depletion of the brain antioxidant glutathione (GSH) may be important in OS-mediated neurodegeneration, though studies of post-mortem brain GSH changes in AD have been inconclusive. Recent in vivo measurements of brain and blood GSH may shed light on GSH changes earlier in the disease. Aim: To quantitatively review in vivo GSH in AD and MCI compared to healthy controls (HC) using meta-analyses. Method: Studies with in vivo brain or blood GSH levels in MCI or AD with a HC group were identified using Medline, PsychInfo, and Embase (1947-June 2020). Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes using random effects models. Outcome measures included brain GSH (Meshcher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) versus non-MEGA-PRESS), and blood GSH (intracellular versus extracellular) in AD and MCI. The Q statistic and Egger’s test were used to assess heterogeneity and risk of publication bias, respectively. Results: For brain GSH, 4 AD (AD=135, HC=223) and 4 MCI (MCI=213, HC=211) studies were included. For blood GSH, 26 AD (AD=1203, HC=1135) and 7 MCI (MCI=434, HC=408) studies were included. Brain GSH overall did not differ in AD or MCI compared to HC; however, the subgroup of studies using MEGA-PRESS reported lower brain GSH in AD (SMD [95%CI] -1.45 [-1.83, -1.06], p<0.001) and MCI (-1.15 [-1.71, -0.59], z=4.0, p<0.001). AD had lower intracellular and extracellular blood GSH overall (-1.10 [-1.58, -0.62], z=4.46, p<0.001). In a subgroup analysis, intracellular GSH was lower in MCI (-0.66 [-1.11, -0.21], p=0.025). Heterogeneity was observed throughout (I² >85%) and not fully accounted by subgroup analysis. Egger’s test indicated risk of publication bias. Conclusion: Blood intracellular GSH decrease is seen in MCI, while both intra- and extracellular decreases were seen in AD. Brain GSH is decreased in AD and MCI in subgroup analysis. Potential bias and heterogeneity suggest the need for measurement standardization and additional studies to explore sources of heterogeneity.
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Measurement of chiral thiol compounds such as glutathione (GSH), cysteine (Cys), and homocysteine (Hcy) in human serum plays an important role in the early diagnosis and warning of cardiovascular disease, neurodegenerative disease, and cancer. We developed a novel chiral mass spectrometry derivatization reagent, (R)-(5-(3-isothiocyanatopyrrolidin-1-yl)-5-oxopentyl) triphenylphosphonium (NCS-OTPP), with triphenylphosphine (TPP) as a basic structure carrying a permanent positive charge for the diastereomeric separation of chiral thiol compounds by ultrahigh-performance liquid chromatography coupled to quadrupole-Orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS). A novel method was developed for simultaneous determination of three kinds of chiral thiol compounds based on the NCS-OTPP derivatization method. Three kinds of chiral thiol compounds on a YMC Triart C18 (2.0 × 150 mm, 1.9 μm) column with Rs were 1.56–1.68. The protonated precursor to product ion transitions monitored for GSH was m/z 780.16→747.24/473.18, Cys was m/z 594.20→561.18/473.18, and Hcy was m/z 608.21→575.19/473.18. An excellent linearity for all the analytes with correlation coefficients ≥ 0.9995 and suitable precision with inter-day and intra-day coefficients of variation RSDs was 0.83–4.06% and 0.95–3.11%. Satisfactory accuracy with recoveries between 83.73 and 103.35% was observed. The limit of detection (S/N = 3) was 2.4–7.2 fmol. Furthermore, the method was successfully applied to the simultaneous determination of three kinds of free and total thiol compounds in serum from 10 healthy volunteers at normal and stress states.
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The red-pigmented astaxanthin (3,-3’-dihydroxy-?,?-carotene-4,4’-dione) were commonly found in marine algae and aquatic animals such as shrimp, lobster, and trout. These pigments are produced as secondary metabolites which fall in arytenoids under class xanthophylls. Synthetic astaxanthin has a wide range of commercial applications such as color additives, usage in cosmetics and immune-boosters. In aquaculture, supplementing synthetic astaxanthin as feed, enhances skin pigmentation which possesses commercial importance. However, synthetic astaxanthin is not highly efficient compared to naturally derived counter forms. On the other hand, humans should only depend on microbial and aquatic sources for their dietary intake of natural astaxanthin. Being a powerful antioxidant, natural astaxanthin is called as king of antioxidants which has scavenging activity 6000 times stronger than vitamin C and 50 times more powerful than vitamin E in protecting cell membranes. It also has a single oxygen quenching activity up to 800 times stronger than coenzyme Q, 550 times more powerful than green tea catechins, 4.9 times stronger than beta-carotene and three times stronger than lute in. Furthermore, researchers revealed that this carotenoid has the capacity to alleviate tumor activity, protecting against lipid per oxidation, free radicals, oxidative damage to LDL-cholesterol and UV light affects on cell membranes and tissues. Also, it is mainly recommended for curing the macular degeneration of cataracts. Anti-aging properties of astaxanthin improve skin health by reducing wrinkles and repairs the UV-induced DNA damage in human cells. Interestingly, the ability of astaxanthin in crossing the blood-brain barrier has brought this compound to limelight as a potential target in treating neurodegenerative diseases including Parkinson's and Alzheimer's disease. Hence, in this review, we are mainly focusing on the therapeutic usage of astaxanthin in neurodegenerative diseases.
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As a kind of bioactive sulfur species, biothiols (Cys, Hcy, and GSH) play an irreplaceable role in regulating the redox balance of life processes. Because of their similar chemical structures and properties, a sulfydryl group, and an amino group, it is an important challenge to distinguish two or more of them at the same time. Herein, a fluorescent sensor (NTPC) based on the coumarin structure was developed to discriminate Cys/Hcy and GSH simultaneously. The sensor has no fluorescence due to the d-PET effect but displays strong fluorescence after its reaction with biothiols. There are two potential reaction sites (nitrophenyl sulfide group and aldehyde group) in the structure of NTPC, resulting in different fluorescent signal changes after reacting with biothiols (green for Cys and Hcy and red for GSH). Under double-wavelength excitation, the sensor shows low background fluorescence, high selectivity, and low detection limits toward biothiols. Moreover, the sensor can be used to discriminate different biothiols (Cys/Hcy and GSH) in cells and zebra fish by different fluorescence signals with low toxicity and might provide a promising tool for studying the roles of different biothiols in various physiological and pathological processes.
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Introduction . To date, age and sex differences have been established for many biochemical parameters. Gender differences in indicators for systems such as antioxidant, thiol-disulfide, oxidative stress and inflammation systems are absent or under study. The aim of the study was to identify gender differences in biochemical parameters reflecting the functioning of antioxidant systems of the body and free radical oxidation in workers of metallurgical production, in contact with harmful production factors. Materials and methods. The blood of men and women working at the metallurgical enterprise of the Nizhny Novgorod region (n=80) under the influence of a complex of physical and chemical production factors was studied. Total oxidative stress, total antioxidant capacity of serum, glutathione levels were studied by photometric biochemical methods. Levels of C-reactive protein and 8-hydroxy–2-deoxyguanosine were studied by ELISA. Results. The average amount of peroxides in the serum of women exceeded 1.6 times this figure in men. In the group of men, the content of 8-Ondg was higher by 26% (p=0.012), the level of GS-by 12% (p=0.019), the activity of SOD — by 1.5–2 times (p=0.0001), the level of CRP — by 2 times (p=0.008) compared to similar indicators in women. Conclusions . Studies of gender differences in workers under the influence of harmful production factors will allow more effective approach to the etiology, treatment and prognosis of production-related diseases. Indicators of oxidative stress and antioxidant protection can be indicators of the health of workers under the influence of harmful industrial factors and be important in the prevention of diseases associated with oxidative stress.
Chapter
Although direct quantification of reactive oxygen species (ROS) is challenging, their interacting partners can readily be used for assessment of redox status in living organisms. Biothiols are molecules directly involved in scavenging of ROS, and their levels reflect the amount of oxidative burden. However, even analysis of these molecules has its obstacles. Due to their high reactivity, proper derivatization protocol is needed. Here, we present a protocol for LC-MS/MS analysis of the four most significant thiols in plasma using new N-phenylmaleimide derivatization reagent. Both analytical method and sample preparation were thoroughly optimized to provide a method that is fast and straightforward and easily applicable in biomedical research.
Chapter
Oxidative stress has been related to osteoporosis and other pathologies at the bone. Coenzyme Q10 (CoQ10), a lipid-soluble antioxidant present in cell membranes, has been suggested in vitro to reduce intracellular reactive oxygen species (ROS) production at the same time to prevent or reduce osteoclastogenesis. Also, it promotes osteoblast differentiation and proliferation and matrix mineralization. Thus it has been suggested that this effect on osteoclastogenesis could be a consequence of the reduction of intracellular ROS. The protective effect of CoQ10 against bone loss has been also demonstrated in rodents. Age-associated changes in systemic markers of oxidative damage in animals treated with CoQ10 suggest that this antioxidant can reduce not only intracellular ROS alleviating oxidative damage but also osteoclastogenesis and bone resorption triggered by different signals. Additionally, it has been suggested that oxidative stress is the main mechanism explaining bone alterations both in aged rodents and in those with acute sex steroid deficiency.
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Herein, a novel bimodal ratiometric probe for sensitive and selective detection of biothiols (including glutathione (GSH), cysteine (Cys) and homocysteine (Hcys)) was constructed, which was based on the redox reaction between manganese dioxide nanoflakes (MnO2 NFs) and rhodamine (RhB) and biothiols. When MnO2 NFs was added into RhB solution, RhB was oxidized to a series of derivatives, accompanying with the colorimetric color changing from purple to light pink and fluorescence changing from red to green. In the presence of GSH, Cys or Hcys, they could reduce MnO2 NFs to Mn²⁺, thereby preventing the following oxidization of RhB and the corresponding color and fluorescence changes. The absorption intensity ratio and fluorescence intensity ratio showed good linear relationships with the concentrations of biothiols. The colorimetric detection limits for GSH, Cys and Hcys were 0.057 μM, 0.140 μM and 0.087 μM, respectively. And the fluorescence detection limits were 0.177 μM, 0.282 μM and 0.161 μM. More importantly, this probe was successfully applied to monitor the concentration of GSH/Cys/Hcys in human serum samples, with satisfactory recovery. Thus, this MnO2 NFs-RhB platform can potentially be a candidate for the detection of biothiols.
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The potential of exosomes as biomarker resources for diagnostics and even for therapeutics has intensified research in the field, including in the context of Alzheimer´s disease (AD). The search for disease biomarkers in peripheral biofluids is advancing mainly due to the easy access it offers. In the study presented here, emphasis was given to the bioinformatic identification of putative exosomal candidates for AD. The exosomal proteomes of cerebrospinal fluid (CSF), serum and plasma, were obtained from three databases (ExoCarta, EVpedia and Vesiclepedia), and complemented with additional exosomal proteins already associated with AD but not found in the databases. The final biofluids’ proteomes were submitted to gene ontology (GO) enrichment analysis and the exosomal Aβ-binding proteins that can constitute putative candidates were identified. Among these candidates, gelsolin, a protein known to be involved in inhibiting Abeta fibril formation, was identified, and it was tested in human samples. The levels of this Aβ-binding protein, with anti-amyloidogenic properties, were assessed in serum-derived exosomes isolated from controls and individuals with dementia, including AD cases, and revealed altered expression patterns. Identification of potential peripheral biomarker candidates for AD may be useful, not only for early disease diagnosis but also in drug trials and to monitor disease progression, allowing for a timely therapeutic intervention, which will positively impact the patient’s quality of life.
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Mild cognitive impairment (MCI) is generally referred to the transitional zone between normal cognitive aging and early dementia or clinically probable Alzheimer’s disease (AD). Most individuals with amnestic MCI eventually develop AD, which suggests that MCI may be the earliest phase of AD. Oxidative stress is observed in brain from subjects with both AD and MCI. Among others, two possibilities for elevated oxidataive stress are decreased activity or elevated expression of antioxidant enzymes, the latter as a response to the former. Accordingly, in the current study, the protein levels and activity of some antioxidant enzymes in the hippocampus of control and MCI brain were measured using Western blot analysis and spectrophotometric methods, respectively. Alterations in the levels and activity of a number of antioxidant enzymes in MCI brain compared to age-matched controls were found. These results are consistent with the hypothesis that oxidative stress may be an early event in the progression of amnestic MCI to AD.
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Human brain levels of glutathione (GSH), glutathione disulfide (GSSG), and vitamin E were measured in neurologically normal control patients and two, groups of patients with neurodegeneration: those with Alzheimer’s disease (AD), and AD with some features of Parkinson’s disease (AD-PD). Control brain samples contained GSH levels more than 50 times higher than GSSG. The levels of GSH were highest in the caudate nucleus and lowest in the medulla. In patients with AD or AD-PD, hippocampal levels of GSH were significantly higher than controls. Patients with AD also demonstrated high GSH levels in the midbrain compared to normal. In contrast, patients with AD-PD did not have significantly elevated GSH levels in this site. GSSG levels were not significantly different in any brain region between controls and diseased patients. In control brains, the medulla had higher levels of vitamin E than any other brain region. The caudate nucleus had the lowest levels, which were about half the levels in the medulla. Control levels of vitamin E in the midbrain were about 18.8, μg/g. In AD patients the midbrain levels of vitamin E doubled to 42.3 μg/g. This doubling also occurred in AD-PD patients where midbrain vitamin E levels increased to 44.0 μg/g. These results may indicate that compensatory increases in GSH and vitamin E levels occur following damage to specific brain regions in patients with AD or AD-PD.
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Oxidative stress has been shown to be a triggering event in the pathogenesis of Alzheimer's disease (AD). However, little evidence exists on the role of oxidative imbalance in Mild Cognitive Impairment (MCI), a group with a high risk of progression to AD. We therefore assessed the peripheral blood levels of a broad spectrum of non-enzymatic and enzymatic antioxidant defenses, as well as lipid and protein oxidation markers and nitrogen oxidative species in 85 MCI patients, 42 mild AD patients and 37 age-matched controls. In mild AD patients, the plasma levels of vitamin E were significantly decreased, while the plasma concentration of oxidized glutathione was increased in both MCI and mild AD patients. An increase in plasmatic and erythrocytes oxidative markers was also observed in MCI and mild AD patients as compared to controls. In both patients groups, increased levels of plasma antioxidants were found in females, whereas apolipoprotein E epsilon4 allele carriers showed higher indices of intracellular oxidative markers. Moreover, in MCI patients, cognitive function positively correlates with antioxidant levels. This study shows that most of the oxidative changes found in mild AD patients are already present in the MCI group, and that progression to AD might be accompanied by antioxidant depletion.
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Human brain levels of glutathione (GSH), glutathione disulfide (GSSG), and vitamin E were measured in neurologically normal control patients and two groups of patients with neurodegeneration: those with Alzheimer's disease (AD), and AD with some features of Parkinson's disease (AD-PD). Control brain samples contained GSH levels more than 50 times higher than GSSG. The levels of GSH were highest in the caudate nucleus and lowest in the medulla. In patients with AD or AD-PD, hippocampal levels of GSH were significantly higher than controls. Patients with AD also demonstrated high GSH levels in the midbrain compared to normal. In contrast, patients with AD-PD did not have significantly elevated GSH levels in this site. GSSG levels were not significantly different in any brain region between controls and diseased patients. In control brains, the medulla had higher levels of vitamin E than any other brain region. The caudate nucleus had the lowest levels, which were about half the levels in the medulla. Control levels of vitamin E in the midbrain were about 18.8 micrograms/g. In AD patients the midbrain levels of vitamin E doubled to 42.3 micrograms/g. This doubling also occurred in AD-PD patients where midbrain vitamin E levels increased to 44.0 micrograms/g. These results may indicate that compensatory increases in GSH and vitamin E levels occur following damage to specific brain regions in patients with AD or AD-PD.
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to investigate blood markers of oxidative stress, and enzymatic and non-enzymatic antioxidants in normally nourished elderly people with Alzheimer's disease. case-control study. twenty patients with Alzheimer's disease and 23 elderly control subjects, living at home, free from disease and not undergoing any treatment known to have a strong influence on blood oxidative stress markers or antioxidant defence systems. we performed a nutritional evaluation, including anthropometric and biological measures and a 3-day dietary record. We determined concentrations of antioxidant vitamins (alpha-tocopherol, retinol) and malondialdehyde in plasma and erythrocytes. We also measured erythrocyte enzymatic activities of glutathione peroxidase and copper-zinc superoxide dismutase. the two groups were similar in age, body mass index, dietary record and serum albumin concentration. After adjustment for age, sex and cardiovascular co-morbidity, mean plasma concentration of alpha-tocopherol was lower in those with Alzheimer disease than in control subjects (15+/-3.5 mg/l compared with 18.2+/-3.5; P=0.002), as was the mean plasma concentration of retinol (0.54+/-0.2 mg/l vs 0.7+/-0.2; P=0.014). The mean concentration of free plasma malondialdehyde was higher in those with Alzheimer's disease (0.70+/-0.2 mmol/l vs 0.5+/-0.1; P=0.036). In Alzheimer disease patients, free plasma malondialdehyde concentrations were inversely correlated with levels of alpha-tocopherol (P=0.002) and retinol (P=0.025). Erythrocyte levels of vitamins and enzymatic activities were similar in the two groups. lower plasma concentrations of alpha-tocopherol and retinol in normally nourished elderly patients with Alzheimer's disease than in controls could suggest that these antioxidant vitamins had been consumed as a result of excessive production of free radicals.
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It has now been established through multiple lines of evidence that oxidative stress is an early event in Alzheimer's disease. occurring prior to the canonical cytopathology. Thus, oxidative stress likely plays a key pathogenic role in the disease and is clearly involved in the cell loss and other neuropathology associated with Alzheimer's disease as demonstrated by the large number of metabolic signs of oxidative stress and by markers of oxidative damage. One puzzling observation, however, is that oxidative damage decreases with disease progression, such that levels of markers of rapidly formed oxidative damage, which are initially elevated. decrease as the disease progresses to advanced Alzheimer's disease. This finding indicates that reactive oxygen species not only cause damage to cellular structures but also provoke cellular responses, such as the compensatory upregulation of antioxidant enzymes found in vulnerable neurons in Alzheimer's disease. Not surprisingly, stress-activated protein kinase pathways, which are activated by oxidative stress, are extensively activated during Alzheimer's disease. In this review, we present the evidence of oxidative stress and compensatory responses that occur in Alzheimer's disease with a particular focus on the roles and mechanism of activation of stress-activated protein kinase pathways.
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Zinc, iron and copper are concentrated in senile plaques of Alzheimer disease. Copper and iron catalyze the Fenton-Haber-Weiss reaction, which likely contributes to oxidative stress in neuronal cells. In this study, we found that ascorbate oxidase activity and the intensity of ascorbate radicals measured using ESR spectroscopy, generated by free Cu(II), was decreased in the presence of amyloid-beta (Abeta), the major component of senile plaques. Specifically, the ascorbate oxidase activity was strongly inhibited (85% decrease) in the presence of Abeta1-16 or Abeta1-42, whereas it was only slightly inhibited in the presence of Abeta1-12 or Abeta25-35 (<20% inhibition). Ascorbate-dependent hydroxyl radical generation by free Cu(II) decreased in the presence of Abeta in the identical order of Abeta1-42, Abeta1-16 > Abeta1-12 and was abolished in the presence of 2-fold molar excess glycylhystidyllysine (GHK). Ascorbate oxidase activity and ascorbate-dependent hydroxyl radical generation by free Fe(III) were inhibited by Abeta1-42, Abeta1-16, and Abeta1-12. Although Cu(II)-Abeta shows a significant SOD-like activity, the rate constant for the reaction of superoxide with Cu(II)-Abeta was much slower than that with SOD. Overall, our results suggest that His6, His13, and His14 residues of Abeta1-42 control the redox activity of transition metals present in senile plaques.
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We have determined various biomarkers in the peripheral blood of Alzheimer, Parkinson and vascular dementia patients by comparing the samples with those of first-degree relatives and control subjects. Our results, together with correlation studies using data from the Mini-Mental State Examination (MMSE), suggest that the clinical evaluation of the nitrite (NOx) concentration in Alzheimer patients should be complemented by assays of protein carbonyls (PCs) levels, the ratio of reduced to oxidized glutathione (GSH/GSSG) in plasma, PCs in erythrocytes and PCs and calcium content in leukocytes. For Parkinson patients it would be useful to determine NOx, thiobarbituric-acid reactive substances (TBARS) and PCs in erythrocytes, and NOx and TBARS en leukocytes. For vascular-demented (VD) patients, determination of NOx, Cu, and GSH/GSSG in plasma and TBARS, and PCs in erythrocytes together with PCs in leukocytes should be assayed. Relatives of Alzheimer patients showed alterations in plasma Se and Zn concentrations, catalase (CAT) activity in erythrocytes and calcium content in leukocytes as possible predictive markers of the disease. Relatives of Parkinson patients showed elevated levels of NOx in leukocytes. In the case of vascular-demented patients we suggest NOx, GSH/GSSG and α-tocopherol in plasma, the CAT/superoxide dismutase ratio in erythrocytes and TBARS, GSSG and glutathione reductase in leukocytes as predictive markers. Large-scale longitudinal population-based studies using these suggested biomarkers are necessary in order to assess their level of reliability and specificity in clinical practice.
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A number of studies reported that oxidative and nitrosative damage may be important in the pathogenesis of Alzheimer's disease (AD). However, whether oxidative damage precedes, contributes directly, or is secondary to AD pathogenesis is not known. Amnestic mild cognitive impairment (MCI) is a clinical condition that is a transition between normal aging and dementia and AD, characterized by a memory deficit without loss of general cognitive and functional abilities. Analysis of nitrosative stress in MCI could be important to determine whether nitrosative damage directly contributes to AD. In the present study, we measured the level of total protein nitration to determine if excess protein nitration occurs in brain samples from subjects with MCI compared to that in healthy controls. We demonstrated using slot blot that protein nitration is higher in the inferior parietal lobule (IPL) and hippocampus in MCI compared to those regions from control subjects. Immunohistochemistry analysis of hippocampus confirmed this result. These findings suggest that nitrosative damage occurs early in the course of MCI, and that protein nitration may be important for conversion of MCI to AD.
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Oxidative stress is at the forefront of Alzheimer disease (AD) research. While its implications in the characteristic neurodegeneration of AD are vast, the most important aspect is that it seems increasingly apparent that oxidative stress is in fact a primary progenitor of the disease, and not merely an epiphenomenon. Moreover, evidence indicates that a long "dormant period" of gradual oxidative damage accumulation precedes and actually leads to the seemingly sudden appearance of clinical and pathological AD symptoms, including amyloid-beta deposition, neurofibrillary tangle formation, metabolic dysfunction, and cognitive decline. These findings provide important insights into the development of potential treatment regimens and even allude to the possibility of a preventative cure. In this review, we elaborate on the dynamic role of oxidative stress in AD and present corresponding treatment strategies that are currently under investigation.
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Mild cognitive impairment (MCI) is a nosological entity proposed as an intermediate state between normal aging and dementia. MCI seems to represent an early stage of Alzheimer's disease (AD) and there is a great interest in the relationship between MCI and the progression to AD. Some studies have demonstrated an accumulation of products of free radical damage in the central nervous system and in the peripheral tissues of subjects with AD or mild cognitive impairment. The aim of the present work was to evaluate the serum levels of some enzymatic antioxidant defences like superoxide dismutase (SOD) and glutathione peroxidase (GPX), as well as lipid peroxidation markers like MDA (malondialdehyde), in MCI and AD patients, compared with age-matched healthy controls. The subjects of this study (45 patients) consisted of 15 individuals with mild cognitive impairment (MCI), 15 with Alzheimer's disease (AD) and 15 healthy age-matched controls. Biochemical analyses showed a similar decrease of the main enzymatic antioxidant defences (SOD and GPX) and increased production of lipid peroxidation marker (MDA) in the serum of the MCI and AD patients, compared to age-matched control group. This study clearly demonstrates that oxidative stress damage occurs in patients with MCI and AD. Moreover, some enzymatic markers of oxidative stress are similar in MCI and AD patients, suggesting that oxidative damage could be one important aspect for the onset of AD.
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Alzheimer's disease (AD) is the most common type of dementia in the elderly. Products of oxidative and nitrosative stress (OS and NS, respectively) accumulate with aging, which is the main risk factor for AD. This provides the basis for the involvement of OS and NS in AD pathogenesis. OS and NS occur in biological systems due to the dysregulation of the redox balance, caused by a deficiency of antioxidants and/or the overproduction of free radicals. Free radical attack against lipids, proteins, sugars and nucleic acids leads to the formation of bioproducts whose detection in fluids and tissues represents the currently available method for assessing oxidative/nitrosative damage. Post-mortem and in-vivo studies have demonstrated an accumulation of products of free radical damage in the central nervous system and in the peripheral tissues of subjects with AD or mild cognitive impairment (MCI). In addition to their individual role, biomarkers for OS and NS in AD are associated with altered bioenergetics and amyloid-beta (Abeta) metabolism. In this review we discuss the main results obtained in the field of biomarkers of oxidative/nitrosative stress in AD and MCI in humans, in addition to their potential role as a tool for diagnosis, prognosis and treatment efficacy in AD.
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The total glutathione content of biological samples is conveniently determined with an enzymatic recycling assay based on glutathione reductase (F. Tietze, 1969, Anal. Biochem.27, 502–522). In the original and several subsequent descriptions of this procedure, glutathione disulfide is selectively determined by assaying samples in which glutathione is masked by pretreatment with N-ethylmaleimide. Since N-ethylmaleimide is a potent inhibitor of glutathione reductase, it is necessary to remove excess reagent; the procedures used are laborious and contribute significantly to experimental error. It is reported here that 2-vinylpyridine is a much better reagent for the derivitization of glutathione. In contrast to N-ethylmaleimide, 2-vinylpyridine does not inhibit glutathione reductase significantly and therefore need not be removed from the sample solutions. 2-Vinylpyridine reacts with glutathione at slightly acidic pH values where spontaneous formation of glutathione disulfide is minimal. It is demonstrated that the total glutathione concentration in mouse plasma is substantially higher than generally reported and that glutathione disulfide constitutes less than 30% of the total glutathione present.
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The enzyme catalase is present in relatively small amounts in neural tissue. A standard spectrophotometric assay for catalase has been modified to make it suitable both for automated assay with a plate reader and for the analysis of neural cell cultures. Catalase activity is determined by measuring residual hydrogen peroxide after incubation with the enzyme. Ferrous ions and thiocyanate are used for the spectrophotometric determination of hydrogen peroxide. The stable visible absorption of ferrithiocyanate can be measured either with a plate reader or a spectrophotometer. The method assays catalase activity from single wells of a tissue culture plate containing 2-3 mg of embryonic rat mesencephalon.
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Defenses against free radical damage were determined in red blood cells and plasma from 40 patients with dementia of the Alzheimer-type (DAT) and 34 aged control subjects with normal cognitive function. No crude significant difference in erythrocyte copper-zinc superoxide dismutase (E-CuZnSOD), seleno-dependent glutathione peroxidase (E-GSH-Px), glutathione reductase (E-GSSG-RD) activities, and selenium (Se) concentration was found between DAT cases and control subjects. The peroxidation products evaluated in plasma by the thiobarbituric-reactive material (TBARS) were at the same level in the DAT group as compared to controls. In the DAT group, plasma GSH-Px (P-GSH-Px) activity and plasma Se (P-Se) were negatively correlated with age (r = -0.58; p < 0.001 and r = -0.63; p < 0.001 respectively). Moreover, erythrocyte GSH-Px activity and Se were also negatively correlated with age (r = -0.40; p < 0.01 and r = -0.46; p < 0.01, respectively). No significant correlation with age was observed in the controls. When controlling for age, a significant increase for P-GSH-Px activity and P-Se was observed in DAT patients as compared to controls. These significant differences mostly appeared in DAT subjects under 80 years. Some correlations were only observed in the DAT group such as P-GSH-Px and E-GSH-Px (r = +0.68; p < 0.001); P-GSH-Px and E-Se (r = +0.79; p < 0.001). Correlations between P-GSH-Px and P-Se, E-GSH-Px and P-Se, and P-Se with E-Se are greater in the DAT group (r = +0.84; p < 0.001; r = +0.76; p < 0.001 and r = 0.75; p < 0.001) than in the control group (r = 0.54, pI < 0.01; r = 0.43, p < 0.01 and r = +0.34, p < 0.05 respectively). The fact that first -- a significant increase in P-GSH-Px and P-Se, second -- some modifications in the relationships between antioxidant parameters, and third -- age-dependent decreases of glutathione-peroxidase activities and their cofactor, appeared only in the DAT group suggest that DAT is associated with an oxidative stress due to an imbalance between reactive oxygen species and the peripheral antioxidant opposing forces.
Article
The cause of neuronal loss in patients with idiopathic Parkinson's disease is unknown. Oxidative stress and complex I deficiency have both been identified in the substantia nigra in Parkinson's disease but their place in the sequence of events resulting in dopaminergic cell death is uncertain. We have analysed respiratory chain activity, iron and reduced glutathione concentrations in Parkinson's disease substantia innominata and in the cingulate cortex of patients with Parkinson's disease, Alzheimer's disease and dementia with Lewy bodies to investigate their association with neuronal death and Lewy body formation. No abnormalities of mitochondrial function, iron or reduced glutathione levels were identified in Parkinson's disease substantia innominata or cingulate cortex. Mitochondrial function also appeared to be unchanged in cingulate cortex from patients with Alzheimer's disease and from patients with dementia with Lewy bodies, however, iron concentrations were mildly increased in both, and reduced glutathione decreased only in Alzheimer's disease. These results confirm the anatomic specificity of the complex I deficiency and decreased levels of reduced glutathione within the Parkinson's disease brain and suggest that these parameters are not associated with cholinergic cell loss in Parkinson's disease nor with Lewy body formation in this or other diseases. We propose that our data support a 'two-hit' hypothesis for the cause of neuronal death in Parkinson's disease.
Article
The blood redox status of probable Alzheimer's Disease (AD) patients and control subjects with distinct Apo E genotypes was investigated. It was assessed by measuring the levels of hydroperoxides (MDA) in plasma and erythrocytes, the levels of the antioxidant defense system (enzymatic and non-enzymatic) in plasma, erythrocytes, platelets and leukocytes, the activities of catechol-O-methyltransferase (COMT) in erythrocytes and monoamine oxidase-B (MAO-B) in platelets and also the activity of the mitochondrial respiratory chain in leukocytes. No significant differences were found between the Apo E genotype and MDA, uric acid, vitamin E and reduced-glutathione (GSH) levels in plasma; MDA, vitamin E, GSH, superoxide-dismutase (SOD), glutathione-peroxidase (GSH-Px) and COMT levels in erythrocytes; vitamin E levels in the platelets of AD patients and control subjects. However, the uric acid levels in plasma and the COMT levels in erythrocytes of AD patients and control subjects with the epsilon4 allele were significantly lower than those observed in control subjects without the epsilon4 allele. Moreover, the duraquinol oxidation level in leukocytes of AD patients with the epsilon4 allele was significantly higher than that in AD patients without the epsilon4 allele and control subjects with and without the epsilon4 allele. The meaning of these results is discussed in terms of involvement of oxidative stress in the etiopathogenesis of AD.
Article
Recently, we demonstrated a significant increase of an oxidized nucleoside derived from RNA, 8-hydroxyguanosine (8OHG), and an oxidized amino acid, nitrotyrosine in vulnerable neurons of patients with Alzheimer disease (AD). To determine whether oxidative damage is an early- or end-stage event in the process of neurodegeneration in AD, we investigated the relationship between neuronal 8OHG and nitrotyrosine and histological and clinical variables, i.e. amyloid-beta (A beta) plaques and neurofibrillary tangles (NFT), as well as duration of dementia and apolipoprotein E (ApoE) genotype. Our findings show that oxidative damage is quantitatively greatest early in the disease and reduces with disease progression. Surprisingly, we found that increases in A beta deposition are associated with decreased oxidative damage. These relationships are more significant in ApoE epsilon4 carriers. Moreover, neurons with NFT show a 40%-56% decrease in relative 8OHG levels compared with neurons free of NFT. Our observations indicate that increased oxidative damage is an early event in AD that decreases with disease progression and lesion formation. These findings suggest that AD is associated with compensatory changes that reduce damage from reactive oxygen.
Article
There are multiple lines of evidence showing that oxidative stress and aberrant mitogenic signaling play an important role in the pathogenesis of Alzheimer disease. However, the chronological relationship between these and other events associated with disease pathogenesis is not known. Given the important role that mitogen-activated protein kinase (MAPK) pathways play in both mitogenic signaling (ERK) and cellular stress signaling (JNK/SAPK and p38), we investigated the chronological and spatial relationship between activated ERK, JNK/SAPK and p38 during disease progression. While all three kinases are activated in the same susceptible neurons in mild and severe cases (Braak stages III-VI), in non-demented cases with limited pathology (Braak stages I and II), both ERK and JNK/SAPK are activated but p38 is not. However, in non-demented cases lacking any sign of pathology (Braak stage 0), either ERK alone or JNK/SAPK alone can be activated. Taken together, these findings indicate that MAPK pathways are differentially activated during the course of Alzheimer disease and, by inference, suggest that both oxidative stress and abnormalities in mitotic signaling can independently serve to initiate, but both are necessary to propagate, disease pathogenesis. Therefore, we propose that both 'hits', oxidative stress and mitotic alterations, are necessary for the progression of Alzheimer disease.
Article
Aminopeptidase A activity (aspartyl aminopeptidase (AspAP) and glutamyl aminopeptidase (GluAP) exerts angiotensinase activity due to its relation to the metabolism of angiotensins in the regional brain renin-angiotensin system (RAS). This activity may also modify the free amino acid pool through the release of N-terminal acidic amino acids. Ethanol (EtOH) exerts profound effects on the brain, inducing important neurological damages. Our purpose is to study the influence of EtOH on AspAP and GluAP activities on basal and K(+)-stimulated conditions, at the synapse level. We used mouse frontal cortex synaptosomes and their incubation supernatant in a Ca(2+)-containing or Ca(2+)-free artificial cerebrospinal fluid. We evaluate the possible contribution of these enzymatic activities on brain blood pressure regulation through RAS and/or the free acidic amino acid pool. The results obtained are correlated with several parameters of oxidative stress, such as free radical generation, lipid peroxidation, and protein oxidation. Under basal conditions, in synaptosomes, EtOH inhibits AspAP and GluAP activities independently of Ca(2+). In the supernatant, however, EtOH differently modulates the two enzyme activities under the various concentrations. Under K(+)-stimulated conditions, EtOH inhibits the K(+)-stimulated increase on AspAP and GluAP differently depending on the presence or absence of Ca(2+) and the concentration of EtOH used. These results invalidate the idea that excess free acidic amino acids could be released by AspAP and GluAP to induce neurodegeneration. The changes in AspAP and GluAP activities as a consequence of EtOH administration and their role in the brain RAS are discussed.
Article
There are many lines of evidence showing that oxidative stress and aberrant mitogenic changes have important roles in the pathogenesis of Alzheimer's disease (AD). However, although both oxidative stress and cell cycle-related abnormalities are early events, occurring before any cytopathology, the relation between these two events, and their role in pathophysiology was, until recently, unclear. However, on the basis of studies of mitogenic and oxidative stress signalling pathways in AD, we proposed a "two-hit hypothesis" which states that although either oxidative stress or abnormalities in mitotic signalling can independently serve as initiators, both processes are necessary to propagate disease pathogenesis. In this paper, we summarise evidence for oxidative stress and abnormal mitotic alterations in AD and explain the two-hit hypothesis by describing how both mechanisms are necessary and invariant features of disease.
Article
The mechanism underlying Alzheimer's disease (AD), an age-related neurodegenerative disease, is still an area of significant controversy. Oxidative damage of macromolecules has been suggested to play an important role in the development of AD; however, the underlying mechanism is still unclear. In this study, we showed that the concentration of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, was decreased in red blood cells from male AD patients compared with age- and gender-matched controls. However, there was no difference in blood GSH concentration between the female patients and female controls. The decrease in GSH content in red blood cells from male AD patients was associated with reduced activities of glutamate cysteine ligase and glutathione synthase, the two enzymes involved in de novo GSH synthesis, with no change in the amount of oxidized glutathione or the activity of glutathione reductase, suggesting that a decreased de novo GSH synthetic capacity is responsible for the decline in GSH content in AD. These results showed for the first time that GSH metabolism was regulated differently in male and female AD patients.
Article
Several studies have shown involvement of peroxynitrite anion, a potent oxidative agent, in Alzheimer's disease (AD) neuropathology. Herein, we assessed in platelets and erythrocytes of AD patients, age-matched and young adults controls: thiobarbituric acid-reactive substances (TBARS) production; superoxide dismutase (SOD), nitric oxide synthase (NOS) and Na,K-ATPase activities; cyclic GMP (cGMP) content, both basal and after sodium nitroprusside (SNP) stimulation. Aging was associated with an increase in TBARS production and NOS activity, a decrease in basal cGMP content and no change in SOD and Na,K-ATPase activities. AD patients, compared to aged controls, have: increase in TBARS production and in NOS, SOD and Na,K-ATPase activities but no alteration in basal cGMP content. SNP increased cGMP platelets production in all groups. In conclusion, we demonstrated in platelets and erythrocytes a disruption in systemic modulation of oxidative stress in aging and with more intensity in AD.