Stress In Alzheimer's Disease Research Articles

Oxidative Stress in Alzheimer's Disease and Mild Cognitive Impairment with High Sensitivity and Specificity

Some studies have determined that oxidative stress is a decisive factor in Alzheimer's disease (AD) and even suggested that it is present in the initial phase of mild cognitive impairment (MCI). The aim of our study was to investigate the process of oxidative stress by measuring the level of malondialdehyde (MDA), the specific activity of two peripheral antioxidant defenses (superoxide dismutase (SOD) and ceruloplasmin), and the level of copper in AD and MCI patients and compare those results with healthy subjects. The sample group consisted of 36 patients with AD, 18 patients with MCI, and 33 healthy aged subjects. Blood samples were obtained from each subject. A significantly higher copper level was found in patients with AD and MCI compared to the control group. The levels of MDA showed a similar trend and were higher in patients from the AD and MCI groups than in the control group. It was found that both studied parameters had positive correlation in the whole studied population (r = 0.340; p = 0.001). A stepwise logistic regression analysis was used to identify an optimal combination of these biomarkers. The optimal biomarker combinations were MDA and SOD with area under the curve of 0.803 (0.691-0.915, CI 95%, p < 0.001) for the diagnosis of AD. The optimal cutpoint yielded 88.0% Sensitivity and 70.0% Specificity. The biomarker combinations predicted AD and were markedly superior to individual biomarkers. Our findings support the hypothesis that oxidative stress might represent a sign of AD pathology and could be an early event in the progression of MCI to AD.

The Role of Oxidative Stress in Alzheimer ’ s Disease

Alzheimer’s disease (AD) is a growing health care epidemic. It is the most common cause of dementia in the elderly and its incidence is rising. The disease is progressive, irreversible and debilitating. It is a great burden on both the patient and their caregivers. The two pathological hallmarks of the disease are aggregated beta-amyloid deposits and hyperphosphorylated neurofibrillary tangles. Although these lesions are found in the AD brain, their role in the pathogenesis leading to clinical dementia is largely unknown and still under debate. Age, which influences theoxidative and inflammatory states of the brain, is the most important risk factor. Recent research has highlighted the important role of oxidative stress, the role of the mitochondria in early disease and inflammation in the underlying molecular mechanism of AD. Oxidative damage predominately involves lipid peroxidation from reactive oxygen species derived from metabolism. Most patients are diagnosed after irreversible damage has been done. A better understanding of the role of these stressors could lead to early therapeutic interventions that better target the cause and have potential to modify disease course. Currently there is no disease modifying treatments available. This literature review highlights current knowledge regarding the role of oxidative stress, how it relates to the pathogenesis of AD and how further research in this field can benefit those who suffer from this debilitating disease.

Deconstructing mitochondrial dysfunction in Alzheimer disease.

There is mounting evidence showing that mitochondrial damage plays an important role in Alzheimer disease. Increased oxygen species generation and deficient mitochondrial dynamic balance have been suggested to be the reason as well as the consequence of Alzheimer-related pathology. Mitochondrial damage has been related to amyloid-beta or tau pathology or to the presence of specific presenilin-1 mutations. The contribution of these factors to mitochondrial dysfunction is reviewed in this paper. Due to the relevance of mitochondrial alterations in Alzheimer disease, recent works have suggested the therapeutic potential of mitochondrial-targeted antioxidant. On the other hand, autophagy has been demonstrated to play a fundamental role in Alzheimer-related protein stress, and increasing data shows that this pathway is altered in the disease. Moreover, mitochondrial alterations have been related to an insufficient clearance of dysfunctional mitochondria by autophagy. Consequently, different approaches for the removal of damaged mitochondria or to decrease the related oxidative stress in Alzheimer disease have been described. To understand the role of mitochondrial function in Alzheimer disease it is necessary to generate human cellular models which involve living neurons. We have summarized the novel protocols for the generation of neurons by reprogramming or direct transdifferentiation, which offer useful tools to achieve this result.

Intracellular Accumulation of Toxic Turn Amyloid-β is Associated with Endoplasmic Reticulum Stress in Alzheimer’s Disease

Amyloid-β protein (Aβ) accumulates in the neurons of Alzheimer’s disease (AD) patients at an early stage of the disease. Recently, we found that Aβ with a toxic turn at positions 22 and 23 accumulates in neurons in AD brain. Here, we studied the accumulation of Aβ, toxic turn Aβ and high-molecular-weight Aβ oligomers in presenilin 1 (PS1) gene-transfected SH-SY5Y cells as well as in the brains of 3xTg-AD mice and AD patients. Immunostaining revealed that accumulation of toxic turn Aβ was promoted in G384A- and I143T-mutant PS1-transfected cells and further enhanced by co-transfection of cells with the Aβ-precursor protein (AβPP) gene. In contrast, accumulation of high-molecular-weight Aβ oligomers was promoted in mutant PS1 cells but attenuated by co-transfection of cells with the AβPP gene. Toxic turn Aβ was detected in the neurons of 3xTg-AD mice aged 2 months, when the mice were cognitively unimpaired. In contrast, high-molecular-weight Aβ oligomers were detected in the neurons of 7-month-old mice, when memory dysfunction is apparent. Furthermore, immunostaining and western blotting for Rab4, Rab6 and GRP78 revealed increased levels of these proteins in mutant PS1 cells and their accumulation in the neurons of 3xTg-AD mice. Remarkably, GRP78 immunoreactivity was increased at 2 months of age. Double-label immunostaining of AD brain revealed an apparent association between toxic turn Aβ and GRP78, an endoplasmic reticulum (ER) stress marker. Intraneuronal accumulation of toxic turn Aβ may be associated with ER stress in the brains of AD model mice and AD patients at an early stage. Keywords: Amyloid-β protein, endoplasmic reticulum stress, GRP78, oligomers, Rab protein, presenilin 1, toxic turn

Molecular Mechanism Aspect of ER Stress in Alzheimer's Disease: Current Approaches and Future Strategies

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by progressive loss of memory and cognitive impairment. Aggregation of amyloid-β (Aβ) peptides is the crucial factor in the onset of AD. The toxic Aβ peptides Aβ40 and Aβ42 are produced from the Aβ precursor protein (APP), a transmembrane protein which is folded and modified in endoplasmic reticulum (ER). ER is the main organelle for the synthesis and processing of nearly all proteins as well as the main cellular source of Ca2+. Under stress conditions, three main ER pathways including inositol-requiring enzyme 1, protein kinase RNA-like ER kinase, and activating transcription factor 6 become activated causing the accumulation of unfolded or misfolded proteins within ER lumen. These pathways manage the stress by regulating the expression of chaperones and enzymes involved in protein folding. Several studies have reported the dysfunction of these stress-sensing pathways in pathological conditions, including neurodegenerative diseases. Recent studies have proposed that neuronal death in AD arises from dysfunction of the ER. Here, we will review recent research findings on the interaction between ER and mitochondria, and its effect on apoptotic pathways. We further provide insights into studies which suggest the role of ER in animal and/or cellular models of AD. Therapeutic strategies that modulate ER could represent a promising approach for prevention or treatment of AD.

Intracellular Accumulation of Toxic Turn Amyloid-β is Associated with Endoplasmic Reticulum Stress in Alzheimer's Disease

Amyloid-β protein (Aβ) accumulates in the neurons of Alzheimer's disease (AD) patients at an early stage of the disease. Recently, we found that Aβ with a toxic turn at positions 22 and 23 accumulates in neurons in AD brain. Here, we studied the accumulation of Aβ, toxic turn Aβ and high-molecular-weight Aβ oligomers in presenilin 1 (PS1) gene-transfected SH-SY5Y cells as well as in the brains of 3xTg-AD mice and AD patients. Immunostaining revealed that accumulation of toxic turn Aβ was promoted in G384A- and I143T-mutant PS1-transfected cells and further enhanced by co-transfection of cells with the Aβ-precursor protein (AβPP) gene. In contrast, accumulation of high-molecular-weight Aβ oligomers was promoted in mutant PS1 cells but attenuated by co-transfection of cells with the AβPP gene. Toxic turn Aβ was detected in the neurons of 3xTg-AD mice aged 2 months, when the mice were cognitively unimpaired. In contrast, high-molecular-weight Aβ oligomers were detected in the neurons of 7-month-old mice, when memory dysfunction is apparent. Furthermore, immunostaining and western blotting for Rab4, Rab6 and GRP78 revealed increased levels of these proteins in mutant PS1 cells and their accumulation in the neurons of 3xTg-AD mice. Remarkably, GRP78 immunoreactivity was increased at 2 months of age. Double-label immunostaining of AD brain revealed an apparent association between toxic turn Aβ and GRP78, an endoplasmic reticulum (ER) stress marker. Intraneuronal accumulation of toxic turn Aβ may be associated with ER stress in the brains of AD model mice and AD patients at an early stage.

Molecular Mechanism Aspect of ER Stress in Alzheimer's Disease: Current Approaches and Future Strategies

Molecular Mechanism Aspect of ER Stress in Alzheimer's Disease: Current Approaches and Future Strategies

JNKing Neurons

JNK3 promotes the generation of β-amyloid and ER stress in Alzheimer’s disease.

Prognostic biomarkers of oxidative stress in Alzheimer’s disease

Prognostic biomarkers of oxidative stress in Alzheimer’s disease

P3‐016: ER stress in Alzheimer's disease and PSP: Common disease mechanism?

P3‐016: ER stress in Alzheimer's disease and PSP: Common disease mechanism?

P1‐293: An investigation of mitochondrial oxidative stress in Alzheimer's disease

Current therapy for Alzheimer's disease (AD) focuses on delaying progression, illustrating the need for more effective therapeutic targets. Increases in reactive oxygen species (ROS) in the brain link multiple hypotheses for the cause of AD. Mouse models display elevations in ROS prior to both Aß plaque and neurofibrillary tangle formation. In particular, elevations in mitochondrial ROS as a result of Aß aggregation have been observed throughout AD pathology. Antioxidant trials have produced mixed results in mouse models and patients, perhaps due to lack of specificity and targeting. Learning and memory deficits are present in the Tg2576 model of AD prior to plaque formation and ROS elevation. In addition, recent studies have linked mitochondria specific antioxidant, superoxide dismutase 2 (SOD2) with recovery of AD pathology in the Tg2576 mouse model of AD. When Tg2576 mice were crossed with mice that overexpress SOD2, (Tg2576/SOD2 mice) both learning and memory impairment as well as plaque burden were improved, indicating that mitochondrial ROS may play a large role in AD pathogenesis. In order to identify the possible source of ROS, we conducted an investigation in vitro using PC12 cells treated with Aß to examine changes in mitochondrial ROS using both cytosolic (DCFH) and mitochondrial (MitoSOX) ROS dyes. We show that Aß1-42 specifically increased ROS from the mitochondria in a dose dependent manner. Mean fluorescence intensity for DCFH was 220.578 [0uM], 278.258 [1uM], and 289.349 [5uM], whereas MitoSOX intensity was 325.17 [0uM], 363.415 [1uM], and 850.718 [5uM]. These results demonstrate both that the source of ROS likely mitochondrial superoxide and its relationship to a sub-lethal concentration of Aß1-42. In addition, using sub-cellular site-specific redox probes directed to the mitochondria we are assessing the contribution of mitochondrial superoxide (mito-cpYFP) and hydrogen peroxide (pHyper-dMito) to the Aß induced ROS burden in neurons. Our findings implicate the development of specific, targeted mitochondrial antioxidants for AD patients. Identifying the sub-cellular source, the specific ROS species produced, and the mechanisms by which increased mitochondrial ROS influence neuronal function in AD will allow for the development of more effective targeted therapeutic interventions to combat the deleterious effects of this devastating disease.

Ameliorating Effect of Ethanol Leaf Extract of Ficus hispida Linn. on Amyloid beta Aβ (25-35) Induced Cognitive Deficits and Oxidative Stress in Alzheimer’s Mice

Ameliorating Effect of Ethanol Leaf Extract of Ficus hispida Linn. on Amyloid beta Aβ (25-35) Induced Cognitive Deficits and Oxidative Stress in Alzheimer’s Mice

Exploring The Molecular Mechanisms Underlying The Efficacy of Mindfulness Based Stress Reduction In Alleviating Psychological Stress in Alzheimer's Disease Caregivers

Caregiving for a dementia patient is associated with an increased risk for emotional distress, depression, dementia, physical health problems and death. Targeting caregivers as the recipients of interventions may greatly improve patient care. Mindfulness Based Stress Reduction (MBSR) is a clinical intervention based on simple meditation practices which have been shown to reduce stress and improve chronic disease outcomes for many different psychological and medical problems. We explored the effectiveness of MBSR at reducing caregiver stress, as measured by psychological and biological markers. We found that MBSR is an effective means to improve the psychological health status of caregivers for dementia patients. Interestingly, we found some of our caregiver participants benefited from MBSR while others did not. Moreover, we identified multiple biomarkers for which contents in the circulating blood were correlated with psychological indices of stress reduction following MBSR and other biomarkers for which baseline blood contents prior to MBSR were predictive of the likelihood of positive response to MBSR. Our observations provide a window into the mechanisms underlying the health benefits of MBSR intervention and provide a logical basis for developing a personalized medicine approach for applying MBSR intervention to a diverse population of caregivers. Supported by discretionary funding to GMP

The role of iron as a mediator of oxidative stress in Alzheimer disease

Iron is both essential for maintaining a spectrum of metabolic processes in the central nervous system and elsewhere, and potent source of reactive oxygen species. Redox balance with respect to iron, therefore, may be critical to human neurodegenerative disease but is also in need of better understanding. Alzheimer disease (AD) in particular is associated with accumulation of numerous markers of oxidative stress; moreover, oxidative stress has been shown to precede hallmark neuropathological lesions early in the disease process, and such lesions, once present, further accumulate iron, among other markers of oxidative stress. In this review, we discuss the role of iron in the progression of AD.

Conformational Altered p53 as an Early Marker of Oxidative Stress in Alzheimer's Disease

In order to study oxidative stress in peripheral cells of Alzheimer's disease (AD) patients, immortalized lymphocytes derived from two peculiar cohorts of patients, referring to early onset AD (EOSAD) and subjects harboured AD related mutation (ADmut), were used. Oxidative stress was evaluated measuring i) the typical oxidative markers, such as HNE Michel adducts, 3 Nitro-Tyrosine residues and protein carbonyl on protein extracts, ii) and the antioxidant capacity, following the enzymatic kinetic of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRD). We found that the signs of oxidative stress, measured as oxidative marker levels, were evident only in ADmut but not in EOSAD patients. However, oxidative imbalance in EOSAD as well as ADmut lymphocytes was underlined by a reduced SOD activity and GRD activity in both pathological groups in comparison with cells derived from healthy subjects. Furthermore, a redox modulated p53 protein was found conformational altered in both EOSAD and ADmut B lymphocytes in comparison with control cells. This conformational altered p53 isoform, named “unfolded p53”, was recognized by the use of two specific conformational anti-p53 antibodies. Immunoprecipitation experiments, performed with the monoclonal antibodies PAb1620 (that recognizes p53wt) and PAb240 (that is direct towards unfolded p53), and followed by the immunoblotting with anti-4-hydroxynonenal (HNE) and anti- 3-nitrotyrosine (3NT) antibodies, showed a preferential increase of nitrated tyrosine residues in unfolded p53 isoform comparing to p53 wt protein, in both ADmut and EOSAD. In addition, a correlation between unfolded p53 and SOD activity was further found. Thus this study suggests that ROS/RNS contributed to change of p53 tertiary structure and that unfolded p53 can be considered as an early marker of oxidative imbalance in these patients.

Mitochondrial- and endoplasmic reticulum-associated oxidative stress in Alzheimer's disease: from pathogenesis to biomarkers.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, affecting several million of people worldwide. Pathological changes in the AD brain include the presence of amyloid plaques, neurofibrillary tangles, loss of neurons and synapses, and oxidative damage. These changes strongly associate with mitochondrial dysfunction and stress of the endoplasmic reticulum (ER). Mitochondrial dysfunction is intimately linked to the production of reactive oxygen species (ROS) and mitochondrial-driven apoptosis, which appear to be aggravated in the brain of AD patients. Concomitantly, mitochondria are closely associated with ER, and the deleterious crosstalk between both organelles has been shown to be involved in neuronal degeneration in AD. Stimuli that enhance expression of normal and/or folding-defective proteins activate an adaptive unfolded protein response (UPR) that, if unresolved, can cause apoptotic cell death. ER stress also induces the generation of ROS that, together with mitochondrial ROS and decreased activity of several antioxidant defenses, promotes chronic oxidative stress. In this paper we discuss the critical role of mitochondrial and ER dysfunction in oxidative injury in AD cellular and animal models, as well as in biological fluids from AD patients. Progress in developing peripheral and cerebrospinal fluid biomarkers related to oxidative stress will also be summarized.

Oxidative stress in Alzheimer's and Parkinson's diseases: insights from the yeast Saccharomyces cerevisiae.

Alzheimer's (AD) and Parkinson's (PD) diseases are the two most common causes of dementia in aged population. Both are protein-misfolding diseases characterized by the presence of protein deposits in the brain. Despite growing evidence suggesting that oxidative stress is critical to neuronal death, its precise role in disease etiology and progression has not yet been fully understood. Budding yeast Saccharomyces cerevisiae shares conserved biological processes with all eukaryotic cells, including neurons. This fact together with the possibility of simple and quick genetic manipulation highlights this organism as a valuable tool to unravel complex and fundamental mechanisms underlying neurodegeneration. In this paper, we summarize the latest knowledge on the role of oxidative stress in neurodegenerative disorders, with emphasis on AD and PD. Additionally, we provide an overview of the work undertaken to study AD and PD in yeast, focusing the use of this model to understand the effect of oxidative stress in both diseases.

Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells

Increasing evidence suggests the toxicity of intracellular amyloid β-protein (Aβ) to neurons, as well as the involvement of oxidative stress in Alzheimer disease (AD). Here we show that normobaric hyperoxia (exposure of cells to 40% oxygen for five days), and consequent activation of macroautophagy and accumulation of Aβ within lysosomes, induced apoptosis in differentiated SH-SY5Y neuroblastoma cells. Cells under hyperoxia showed: (1) increased numbers of autophagic vacuoles that contained amyloid precursor protein (APP) as well as Aβ monomers and oligomers, (2) increased reactive oxygen species production, and (3) enhanced apoptosis. Oxidant-induced apoptosis positively correlated with cellular Aβ production, being the highest in cells that were stably transfected with APP Swedish KM670/671NL double mutation. Inhibition of γ-secretase, prior and/or in parallel to hyperoxia, suggested that the increase of lysosomal Aβ resulted mainly from its autophagic uptake, but also from APP processing within autophagic vacuoles. The oxidative stress-mediated effects were prevented by macroautophagy inhibition using 3-methyladenine or ATG5 downregulation. Our results suggest that upregulation of macroautophagy and resulting lysosomal Aβ accumulation are essential for oxidant-induced apoptosis in cultured neuroblastoma cells and provide additional support for the interactive role of oxidative stress and the lysosomal system in AD-related neurodegeneration.

Neuronal and vascular oxidative stress in Alzheimer's disease.

The brain is a highly metabolically active organ producing large amounts of reactive oxygen species (ROS). These ROS are kept in check by an elaborate network of antioxidants. Although ROS are necessary for signaling and synaptic plasticity, their uncontrolled levels cause oxidation of essential macromolecules such as membrane lipids, nucleic acids, enzymes and cytoskeletal proteins. Indeed, overproduction of ROS and/or failure of the antioxidant network lead to neuronal oxidative stress, a condition associated with not only aging but also Alzheimer’s disease (AD). However, the specific source of excessive ROS production has not yet been identified. On one hand, amyloid beta (Aβ) has been extensively shown to act as an oxidant molecule. On the other hand, oxidative stress has been shown to precede and exacerbate Aβ pathology. This review will address the involvement of oxidative stress in the context of neuronal as well as vascular dysfunction associated with AD.

Biomedical Imaging and Visualization Model of Mitochondrial Dysfunction and Oxidative Stress in Alzheimer Disease

Mitochondrial dysfunction and oxidative stress are among the earliest events linked to Alzheimer Disease and might play a causative role in disease onset and progression. In this paper, a biomedical imaging and visualization model was set to investigate the mitochondrial dysfunction and oxidative stress in Aβ/Cu2+-treated cells, which contribute in a significant manner to bioenergetic failure and mitochondrial dysfunction, by measuring mitochondrial membrane potential, Ca2+, chromatin condensation and ROS. This evaluating method opens a window for analyzing the protective effect of a certain substance in improving mitochondrial function and preventing oxidative stress in AD development.