Oxidatively modified,mitochondria-relevant brain proteins in subjects with Alzheimer disease and mild cognitive impairment

Alzheimer disease (AD) is an age-related neurodegenerative disorder, characterized histopathologically by the presence of senile plaques (SP), neurofibrillary tangles and synapse loss in selected brain regions. Positron emission tomography (PET) studies of glucose metabolism revealed decreased energetics in brain of subjects with AD and arguably its earliest form, mild cognitive impairment (MCI), and this decrease correlated with brain structural studies using MRI. The main component of senile plaques is amyloid beta-peptide (Aβ), a 40–42 amino acid peptide that as oligomers is capable of inducing oxidative stress under both in vitro and in vivo conditions and is neurotoxic. In the mitochondria isolated from AD brain, Aβ oligomers that correlated with the reported increased oxidative stress markers in AD have been reported. The markers of oxidative stress have been localized in the brain regions of AD and MCI that show pathological hallmarks of this disease, suggesting the possible role of Aβ in the initiation of the free-radical mediated process and consequently to the build up oxidative stress and AD pathogenesis. Using redox proteomics our laboratory found a number of oxidatively modified brain proteins that are directly in or are associated with the mitochondrial proteome, consistent with a possible involvement of the mitochondrial targeted oxidatively modified proteins in AD progression or pathogenesis. The precise mechanistic link between mitochondrial oxidative damage and role of oligomeric Aβ has not been explicated. In this review, we discuss the role of the oxidation of mitochondria-relevant brain proteins to the pathogenesis and progression of AD.     

Effect of acupuncture in mild cognitive impairment and Alzheimer disease: a functional MRI study

We aim to clarify the mechanisms of acupuncture in treating mild cognitive impairment (MCI) and Alzheimer disease (AD) by using functional magnetic resonance imaging (fMRI). Thirty-six right-handed subjects (8 MCI patients, 14 AD patients, and 14 healthy elders) participated in this study. Clinical and neuropsychological examinations were performed on all the subjects. MRI data acquisition was performed on a SIEMENS verio 3-Tesla scanner. The fMRI study used a single block experimental design. We first acquired the baseline resting state data in the initial 3 minutes; we then acquired the fMRI data during the procession of acupuncture stimulation on the acupoints of Tai chong and Hegu for the following 3 minutes. Last, we acquired fMRI data for another 10 minutes after the needle was withdrawn. The preprocessing and data analysis were performed using the statistical parametric mapping (SPM8) software. Then the two-sample t-tests were performed between each two groups of different states. We found that during the resting state, brain activities in AD and MCI patients were different from those of control subjects. During the acupuncture and the second resting state after acupuncture, when comparing to resting state, there are several regions showing increased or decreased activities in MCI, AD subjects compared to normal subjects. Most of the regions were involved in the temporal lobe and the frontal lobe, which were closely related to the memory and cognition. In conclusion, we investigated the effect of acupuncture in AD and MCI patients by combing fMRI and traditional acupuncture. Our fMRI study confirmed that acupuncture at Tai chong (Liv3) and He gu (LI4) can activate certain cognitive-related regions in AD and MCI patients.     

DNA-repair in mild cognitive impairment and Alzheimer's disease

While the pathogenesis of the sporadic form of Alzheimer disease (late onset Alzheimer disease, LOAD) is not fully understood, it seems to be clear that a combination of genetic and environmental factors are involved and influence the course of the disease. Among these factors, elevated levels of oxidative stress have been recognized and individual differences in the capacity to deal with DNA damage caused by its effects have been the subject of numerous studies. This review summarizes the research on DNA repair proteins and genes in the context of LOAD pathogenesis and its possible prodromal stage, mild cognitive impairment (MCI). The current status of the research in this field is discussed with respect to methodological issues which might have compromised the outcome of some studies and future directions of investigation on this subject are depicted.     

Heme oxygenase-1 posttranslational modifications in the brain of subjects with Alzheimer disease and mild cognitive impairment

Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Oxidative and nitrosative stress plays a principal role in the pathogenesis of AD. The induction of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system in the brain represents one of the earliest mechanisms activated by cells to counteract the noxious effects of increased reactive oxygen species and reactive nitrogen species. Although initially proposed as a neuroprotective system in AD brain, the HO-1/BVR-A pathophysiological features are under debate. We previously reported alterations in BVR activity along with decreased phosphorylation and increased oxidative/nitrosative posttranslational modifications in the brain of subjects with AD and those with mild cognitive impairment (MCI). Furthermore, other groups proposed the observed increase in HO-1 in AD brain as a possible neurotoxic mechanism. Here we provide new insights about HO-1 in the brain of subjects with AD and MCI, the latter condition being the transitional phase between normal aging and early AD. HO-1 protein levels were significantly increased in the hippocampus of AD subjects, whereas HO-2 protein levels were significantly decreased in both AD and MCI hippocampi. In addition, significant increases in Ser-residue phosphorylation together with increased oxidative posttranslational modifications were found in the hippocampus of AD subjects. Interestingly, despite the lack of oxidative stress-induced AD neuropathology in cerebellum, HO-1 demonstrated increased Ser-residue phosphorylation and oxidative posttranslational modifications in this brain area, suggesting HO-1 as a target of oxidative damage even in the cerebellum. The significance of these findings is profound and opens new avenues into the comprehension of the role of HO-1 in the pathogenesis of AD.     

Biliverdin reductase--a protein levels and activity in the brains of subjects with Alzheimer disease and mild cognitive impairment

Biliverdin reductase-A is a pleiotropic enzyme involved not only in the reduction of biliverdin-IX-alpha into bilirubin-IX-alpha, but also in the regulation of glucose metabolism and cell growth secondary to its serine/threonine/tyrosine kinase activity. Together with heme oxygenase, whose metabolic role is to degrade heme into biliverdin-IX-alpha, it forms a powerful system involved in the cell stress response during neurodegenerative disorders. In this paper, an up-regulation of the biliverdin reductase-A protein levels was found in the hippocampus of the subjects with Alzheimer disease and arguably its earliest form, mild cognitive impairment. Moreover a significant reduction in the phosphorylation of serine, threonine and tyrosine residues of biliverdin reductase-A was found, and this was paralleled by a marked reduction in its reductase activity. Interestingly, the levels of both total and phosphorylated biliverdin reductase-A were unchanged as well as its enzymatic activity in the cerebella. These results demonstrated a dichotomy between biliverdin reductase-A protein levels and activity in the hippocampus of subjects affected by Alzheimer disease and mild cognitive impairment, and this effect likely is attributable to a reduction in the phosphorylation of serine, threonine and tyrosine residues of biliverdin reductase-A. Consequently, not just the increased levels of biliverdin reductase-A, but also its changed activity and phosphorylation state, should be taken into account when considering potential biomarkers for Alzheimer disease and mild cognitive impairment.     

Biliverdin reductase-A protein levels and activity in the brains of subjects with Alzheimer disease and mild cognitive impairment

Biliverdin reductase-A is a pleiotropic enzyme involved not only in the reduction of biliverdin-IX-alpha into bilirubin-IX-alpha, but also in the regulation of glucose metabolism and cell growth secondary to its serine/threonine/tyrosine kinase activity. Together with heme oxygenase, whose metabolic role is to degrade heme into biliverdin-IX-alpha, it forms a powerful system involved in the cell stress response during neurodegenerative disorders. In this paper, an up-regulation of the biliverdin reductase-A protein levels was found in the hippocampus of the subjects with Alzheimer disease and arguably its earliest form, mild cognitive impairment. Moreover a significant reduction in the phosphorylation of serine, threonine and tyrosine residues of biliverdin reductase-A was found, and this was paralleled by a marked reduction in its reductase activity. Interestingly, the levels of both total and phosphorylated biliverdin reductase-A were unchanged as well as its enzymatic activity in the cerebella. These results demonstrated a dichotomy between biliverdin reductase-A protein levels and activity in the hippocampus of subjects affected by Alzheimer disease and mild cognitive impairment, and this effect likely is attributable to a reduction in the phosphorylation of serine, threonine and tyrosine residues of biliverdin reductase-A. Consequently, not just the increased levels of biliverdin reductase-A, but also its changed activity and phosphorylation state, should be taken into account when considering potential biomarkers for Alzheimer disease and mild cognitive impairment.     

Effects of oxidative and nitrosative stress in brain on p53 proapoptotic protein in amnestic mild cognitive impairment and Alzheimer disease

Many studies reported that oxidative and nitrosative stress might be important for the pathogenesis of Alzheimer's disease (AD) beginning with arguably the earliest stage of AD, i.e., as mild cognitive impairment (MCI). p53 is a proapoptotic protein that plays an important role in neuronal death, a process involved in many neurodegenerative disorders. Moreover, p53 plays a key role in the oxidative stress-dependent apoptosis. We demonstrated previously that p53 levels in brain were significantly higher in MCI and AD IPL (inferior parietal lobule) compared to control brains. In addition, we showed that in AD IPL, but not in MCI, HNE, a lipid peroxidation product, was significantly bound to p53 protein. In this report, we studied by means of immunoprecipitation analysis, the levels of markers of protein oxidation, 3-nitrotyrosine (3-NT) and protein carbonyls, in p53 in a specific region of the cerebral cortex, namely the inferior parietal lobule, in MCI and AD compared to control brains. The focus of these studies was to measure the oxidation and nitration status of this important proapoptotic protein, consistent with the hypothesis that oxidative modification of p53 could be involved in the neuronal loss observed in neurodegenerative conditions.     

Antioxidant clinical trials in mild cognitive impairment and Alzheimer's disease

Alzheimer's disease (AD) is a highly disabling progressive neurodegenerative disorder characterized by a steadily growing number of patients, by the absence of a cure for the disease and by great difficulties in diagnosing in the preclinical phase. Progresses in defining the complex etiopathogenesis of AD consider oxidative stress a core aspect as far as both AD onset and progression are concerned. However, clinical trials of antioxidants in AD have brought conflicting conclusions. In this review, we report the main results of clinical trials with antioxidants in mild cognitive impairment (MCI) and AD. Although available data do not warrant the doubtless use of antioxidants in AD, they are characterized by extremely poor comparability and the absence of a substantial clinical benefit of antioxidants in AD is not disproved to date. Furthermore, the role of vascular damage that contributes to oxidative stress in AD should be addressed in testing antioxidant treatments. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.     

Abnormal cortical networks in mild cognitive impairment and Alzheimer's disease

Recently, many researchers have used graph theory to study the aberrant brain structures in Alzheimer's disease (AD) and have made great progress. However, the characteristics of the cortical network in Mild Cognitive Impairment (MCI) are still largely unexplored. In this study, the gray matter volumes obtained from magnetic resonance imaging (MRI) for all brain regions except the cerebellum were parcellated into 90 areas using the automated anatomical labeling (AAL) template to construct cortical networks for 98 normal controls (NCs), 113 MCIs and 91 ADs. The measurements of the network properties were calculated for each of the three groups respectively. We found that all three cortical networks exhibited small-world properties and those strong interhemispheric correlations existed between bilaterally homologous regions. Among the three cortical networks, we found the greatest clustering coefficient and the longest absolute path length in AD, which might indicate that the organization of the cortical network was the least optimal in AD. The small-world measures of the MCI network exhibited intermediate values. This finding is logical given that MCI is considered to be the transitional stage between normal aging and AD. Out of all the between-group differences in the clustering coefficient and absolute path length, only the differences between the AD and normal control groups were statistically significant. Compared with the normal controls, the MCI and AD groups retained their hub regions in the frontal lobe but showed a loss of hub regions in the temporal lobe. In addition, altered interregional correlations were detected in the parahippocampus gyrus, medial temporal lobe, cingulum, fusiform, medial frontal lobe, and orbital frontal gyrus in groups with MCI and AD. Similar to previous studies of functional connectivity, we also revealed increased interregional correlations within the local brain lobes and disrupted long distance interregional correlations in groups with MCI and AD.     

5-Hydroxyindoleacetic acid and homovanillic acid concentrations in cerebrospinal fluid in patients with Alzheimer's disease, depression and mild cognitive impairment

In this study we investigated the cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in Alzheimer (AD) patients (n=75), patients with mild cognitive impairment (MCI, n=9) and patients with depression (n=7). CSF HVA was significantly elevated in AD with depression (Geriatric Depression Scale, 15 point version GDS>5) in comparison to AD without depression (p<0.05, ANOVA) and CSF HVA showed a significant positive correlation with the GDS score of AD-patients (p=0.03, Spearman Rho: 0.38, Spearman Rank Correlation). In the group of AD patients CSF 5-HIAA was positively correlated with cerebrospinal fluid beta-amyloid 1-42 (Abeta42), p<0.05, Spearman Rho: 0.3, Spearman Rank Correlation, but not with CSF tau. Additionally, there was a significant positive correlation between cerebrospinal fluid 5-HIAA and HVA in the group of AD patients (p<0.0001, Rho: 0.47, Spearman Rank correlation). Neither 5-HIAA nor HVA in CSF could differentiate between mild cognitive impairment, depression and AD. The results of this study support the hypothesis that the serotonergic system plays a role in the course of AD. They further suggest an important role of dopamine metabolism in depression within AD patients.     

Impaired platelet mitochondrial activity in Alzheimer's disease and mild cognitive impairment

Mitochondrial abnormalities are found in Alzheimer's disease (AD), but previous reports have not examined at-risk groups. In subjects with AD, mild cognitive impairment (MCI), and non-demented aged controls, platelet and lymphocyte mitochondria were isolated and analyzed for Complexes I, III, and IV of the electron transport chain. Western blots were used to control for differential enrichment of samples. Results demonstrated significant declines in Complexes III and IV in AD, and a significant decline in Complex IV in MCI. This report confirms mitochondrial deficiencies in AD, extends them to MCI, and suggests they are present at the earliest symptomatic stages of disease.     

Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer's disease

Increasing evidence supports a role for oxidative DNA damage in aging and several neurodegenerative diseases including Alzheimer's disease (AD). Attack of DNA by reactive oxygen species (ROS), particularly hydroxyl radicals, can lead to strand breaks, DNA–DNA and DNA–protein cross-linking, and formation of at least 20 modified bases adducts. In addition, α,β-unsaturated aldehydic by-products of lipid peroxidation including 4-hydroxynonenal and acrolein can interact with DNA bases leading to the formation of bulky exocyclic adducts. Modification of DNA bases by direct interaction with ROS or aldehydes can lead to mutations and altered protein synthesis. Several studies of DNA base adducts in late-stage AD (LAD) brain show elevations of 8-hydroxyguanine (8-OHG), 8-hydroxyadenine (8-OHA), 5-hydroxycytosine (5-OHC), and 5-hydroxyuracil, a chemical degradation product of cytosine, in both nuclear and mitochondrial DNA (mtDNA) isolated from vulnerable regions of LAD brain compared to age-matched normal control subjects. Previous studies also show elevations of acrolein/guanine adducts in the hippocampus of LAD subjects compared to age-matched controls. In addition, studies of base excision repair show a decline in repair of 8-OHG in vulnerable regions of LAD brain. Our recent studies show elevated 8-OHG, 8-OHA, and 5,6-diamino-5-formamidopyrimidine in both nuclear and mtDNA isolated from vulnerable brain regions in amnestic mild cognitive impairment, the earliest clinical manifestation of AD, suggesting that oxidative DNA damage is an early event in AD and is not merely a secondary phenomenon.     

Cingulate cortex hypoperfusion predicts Alzheimer's disease in mild cognitive impairment

Background  

Mild cognitive impairment (MCI) was recently described as a heterogeneous group with a variety of clinical outcomes and high risk to develop Alzheimer's disease (AD). Regional cerebral blood flow (rCBF) as measured by single photon emission computed tomography (SPECT) was used to study the heterogeneity of MCI and to look for predictors of future development of AD.     

Targeted metabolomics reveals altered oxylipin profiles in plasma of mild cognitive impairment patients

Introduction and objective

Mild cognitive impairment (MCI) is considered to be a prodromal stage of Alzheimer’s disease (AD), which is the most common type of dementia. Although MCI is a common clinical manifestation in the elderly, the pathology and molecular mechanisms are not fully understood. Oxylipins are a major class of lipid-derived signaling mediators, which have been implicated in the pathology of MCI and AD. In this study, we investigated the changes of oxylipin profiles in plasma of MCI patients.

Methods

We performed a targeted liquid chromatography—mass spectrometry analysis to quantify 49 oxylipins and 4 polyunsaturated fatty acids in plasma samples of 60 clinically diagnosed MCI patients and 56 age- and gender-matched cognitively normal individuals.

Results

We found that the levels of linoleic acid (LA) and 7 oxylipins were significantly altered in MCI patients when compared to the controls. Notably, oxylipins synthesized through 5-lipoxygenase (5-LOX) and cytochrome P450 (CYP450) pathways of arachidonic acid (AA) or LA were elevated in MCI patients, which is in accordance with previously reports that oxylipins from the same pathways were increased in the brain tissues of AD and MCI patients, suggesting the potential correlations of oxylipin changes in 5-LOX and CYP450 pathways between the peripheral blood and the brain tissues in MCI and AD patients.

Conclusion

This study is the first report on plasma oxylipin profiles in MCI patients, and disease-relevant changes of oxylipins and oxylipin pathways were identified. The results represent potentially an efficient method to monitor certain oxylipin changes in the brain tissues of MCI or AD patients.

     

The effects of depression,anxiety and sleep disturbances on cognitive impairment in patients with chronic obstructive pulmonary disease

The purpose of this study was to investigate the effects of depression, anxiety and sleep disturbances on cognitive functions in chronic obstructive pulmonary disease (COPD) patients. In this prospective case-control study, demographic data, smoking history, depression, anxiety, sleep quality and cognitive status of 48 COPD patients and 36 healthy volunteers aged 40–90 years were recorded. The Beck depression inventory (BDI), the Beck anxiety inventory (BAI), and Pittsburgh Sleep Quality Index (PSQI) were used to assess depression, anxiety and sleep quality, respectively in COPD patients. Cognitive performance was studied by the mini-mental state examination. The mean age of patients with COPD was 65.3 ± 9.4 years, and disease duration was 9.6 ± 7.8 years. Male sex ratio, smoking, BDI score, BAI score, total PSQI score, sleep latency, sleep duration, average use of sleep aids and sleep disturbances in patients with COPD were significantly higher than the control group (p < 0.05). When cognitive impairment was compared by age, FVC, FEV, FEV/FVC, PEF values and smoking, no statistically significant relationship was found (p > 0.05). A statistically significant relationship was established between cognitive impairment and severity of disease, presence of anxiety, presence of depression and sleep quality. In our study, we found that sleep disorders, depression and anxiety comorbid with COPD increased cognitive impairment as well as the severity of disease. We believe that this finding is important in terms of reducing the risk of cognitive impairment, preventing misdiagnosis and treatment of the aforementioned comorbid diseases.     

Altered 8-oxoguanine glycosylase in mild cognitive impairment and late-stage Alzheimer's disease brain

Eight-hydroxy-2'-deoxyguanosine (8-OHdG) is increased in the brain in late-stage Alzheimer's disease (LAD) and mild cognitive impairment (MCI). To determine if decreased base-excision repair contributes to these elevations, we measured oxoguanine glycosylase 1 (OGG1) protein and incision activities in nuclear and mitochondrial fractions from frontal (FL), temporal (TL), and parietal (PL) lobes from 8 MCI and 7 LAD patients, and 6 age-matched normal control (NC) subjects. OGG1 activity was significantly (P<0.05) decreased in nuclear specimens of FL, TL, and PL in MCI and LAD and in mitochondria from LAD FL and TL and MCI TL. Nuclear OGG1 protein was significantly decreased in LAD FL and MCI and LAD PL. No differences in mitochondrial OGG1 protein levels were found. Overall, our results suggest that decreased OGG1 activity occurs early in the progression of AD, possibly mediated by 4-hydroxynonenal inactivation and may contribute to elevated 8-OHdG in the brain in MCI and LAD.     

Oxidative stress and APO E polymorphisms in Alzheimer's disease and in mild cognitive impairment

Abstract

A number of evidences indicates oxidative stress as a relevant pathogenic factor in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Considering its recognized major genetic risk factors in AD, apolipoprotein (APO E) has been investigated in several experimental settings regarding its role in the process of reactive oxygen species (ROS) generation. The aim of this work has been to evaluate possible relationships between APO E genotype and plasma levels of selected oxidative stress markers in both AD and MCI patients.

APO E genotypes were determined using restriction enzyme analysis. Plasma levels of oxidative markers, advanced oxidation protein products, iron-reducing ability of plasma and, in MCI, activity of superoxide dismutases were evaluated using spectrophotometric analysis.

We found, compared to controls, increased levels of oxidized proteins and decreased values of plasma-reducing capacity in both AD patients (p < 0.0001) and MCI patients (p < 0.001); the difference between AD and MCI patients was significant only for plasma-reducing capacity (p < 0.0001), the former showing the lowest values. Superoxide dismutase activity was reduced, although not at statistical level, in MCI compared with that in controls. E4 allele was statistically associated (p < 0.05) with AD patients. When comparing different APO E genotype subgroups, no difference was present, as far as advanced oxidation protein products and iron-reducing ability of plasma levels were concerned, between E4 and non-E4 carriers, in both AD and MCI; on the contrary, E4 carriers MCI patients showed significantly decreased (p < 0.05) superoxide dismutase activity with respect to non-E4 carriers.

This study, in confirming the occurrence of oxidative stress in AD and MCI patients, shows how it can be related, at least for superoxide dismutase activity in MCI, to APO E4 allele risk factor.     

Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort

Background  

Pathological brain iron deposition has been implicated as a source of neurotoxic reactive oxygen species in Alzheimer (AD) and Parkinson diseases (PD). Iron metabolism is associated with the gene hemochromatosis (HFE Human genome nomenclature committee ID:4886), and mutations in HFE are a cause of the iron mismetabolism disease, hemochromatosis. Several reports have tested the association of HFE variants with neurodegenerative diseases, such as AD and PD with conflicting results.     

Malondialdehyde, carbonyl proteins and albumin-disulphide as useful oxidative markers in mild cognitive impairment and Alzheimer's disease

The question arises as to whether oxidative stress has a primary role in neurodegeneration or is a secondary end-stage epiphenomenon. The aim of the present study was to determine oxidative stress parameters like malondialdehyde (MDA), carbonyl proteins (CP) and Albumin-disulphide (Alb-SSR) and relate these parameters to the immune parameter neopterin, folic acid and vitamin B12 as vitamins and homocysteine in patients with neuro-degenerative diseases (NDD), namely mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared to an aged matched control group. MDA, CP and Alb-SSR were significantly increased in the NDD group compared to controls, but not vitamin B12, folic acid and neopterin. Significant correlations were found between CP and Alb-SSR, CP and MDA and between MDA and Alb-SSR including patients with NDD and the control group. These results support the hypothesis that oxidative damage to lipids and proteins is an important early event in the pathogenesis of neurodegenerative diseases.