scholarly journals RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3113
Author(s):  
Sanjay Awasthi ◽  
Ashly Hindle ◽  
Neha A. Sawant ◽  
Mathew George ◽  
Murali Vijayan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Gene Networks ◽  
Sensory Function ◽  
Expression Of Genes ◽  
The Impact

The purpose of our study is to understand the role of the RALBP1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer’s disease (AD) pathogenesis. The RALPB1 gene encodes the 76 kDa protein RLIP76 (Rlip). Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. We hypothesized that Rlip may play an important role in maintaining cognitive function. The aim of this study is to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype (WT) and Rlip+/− mice were analyzed for OS markers, expression of genes that regulate mitochondrial fission/fusion, and synaptic integrity. We also examined mitochondrial ultrastructure in brains obtained from these mice and further analyzed the impact of Rlip deficiency on gene networks of AD, aging, stress response, mitochondrial function, and CREB signaling. Our studies revealed a significant increase in the levels of OS markers and alterations in the expression of genes and proteins involved in mitochondrial biogenesis, dynamics and synapses in brain tissues from these mice. Furthermore, we compared the cognitive function of WT and Rlip+/− mice. Behavioral, basic motor and sensory function tests in Rlip+/− mice revealed cognitive decline, similar to AD. Gene network analysis indicated dysregulation of stress-activated gene expression, mitochondrial function and CREB signaling genes in the Rlip+/− mouse brain. Our results suggest that Rlip deficiency-associated increases in OS and mitochondrial dysfunction could contribute to the development or progression of OS-related AD processes.

scholarly journals Role of RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer's Disease

2021 ◽  
Author(s):  
Sanjay Awasthi ◽  
Ashly Hindle ◽  
Neha Sawant ◽  
Mathew George ◽  
Murali Vijayan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Sensory Function ◽  
Expression Of Genes

The purpose of our study is to understand the role of the Ralbp1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer's disease (AD) pathogenesis. The Ralbp1 gene encodes the 76 kDa protein Rlip (aka RLIP76). Previous studies have revealed its role in OS-related cancer. However, Rlip is transcriptionally regulated by EP300, a CREB-binding protein that is important for synaptic plasticity in the brain. Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. OS causes rapid cellular accumulation of Rlip and its translocation from a tubulin-bound complex to the plasma membrane, mitochondria and nucleus. Therefore, Rlip may play an important role in maintaining cognitive function in the face of OS-related injury. This study is aimed to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype and Rlip+/- mice were analyzed for OS markers, expression of genes that regulate mitochondrial fission/fusion, and synaptic integrity. We also examined mitochondrial ultrastructure in mouse brains obtained from these mice and further analyzed the impact of Rlip deficiency on gene networks of AD, aging, inhibition of stress-activated gene expression, mitochondrial function, and CREB signaling. Our studies revealed a significant increase in the levels of OS markers and alterations in the expression of genes and proteins involved in mitochondrial biogenesis, dynamics and synapses in brain tissues of these mice. Furthermore, we compared the cognitive function of wildtype and Rlip+/- mice. Behavioral, basic motor and sensory function tests in Rlip+/- mice revealed cognitive decline, similar to AD. Gene network analysis indicated dysregulation of stress-activated gene expression, mitochondrial function, and CREB signaling genes in the Rlip+/- mouse liver. Our results suggest that the Rlip deficiency-associated increase in OS and mitochondrial dysfunction could contribute to the development of OS-related AD processes. Therefore, the restoration of Rlip activity and endogenous cytoprotective mechanisms by pharmacological interventions is a novel approach to protect against AD.

scholarly journals Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Afzal Misrani ◽  
Sidra Tabassum ◽  
Li Yang
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Morphology ◽  
Therapeutic Approaches ◽  
The Impact ◽  
And Oxidative Stress

Mitochondria play a pivotal role in bioenergetics and respiratory functions, which are essential for the numerous biochemical processes underpinning cell viability. Mitochondrial morphology changes rapidly in response to external insults and changes in metabolic status via fission and fusion processes (so-called mitochondrial dynamics) that maintain mitochondrial quality and homeostasis. Damaged mitochondria are removed by a process known as mitophagy, which involves their degradation by a specific autophagosomal pathway. Over the last few years, remarkable efforts have been made to investigate the impact on the pathogenesis of Alzheimer’s disease (AD) of various forms of mitochondrial dysfunction, such as excessive reactive oxygen species (ROS) production, mitochondrial Ca2+ dyshomeostasis, loss of ATP, and defects in mitochondrial dynamics and transport, and mitophagy. Recent research suggests that restoration of mitochondrial function by physical exercise, an antioxidant diet, or therapeutic approaches can delay the onset and slow the progression of AD. In this review, we focus on recent progress that highlights the crucial role of alterations in mitochondrial function and oxidative stress in the pathogenesis of AD, emphasizing a framework of existing and potential therapeutic approaches.

scholarly journals Effect of Endurance Exercise and MitoQ Intake on Tau Hyperphosphorylation, Oxidative Stress, Antioxidant Modulating Factors, Mitochondrial Function, and Cognitive Function in Alcl3-Induced Alzheimer’s Disease Animal Model

2021 ◽  
Vol 30 (3) ◽  
pp. 396-406
Author(s):  
Jin-Hue Jeong ◽  
Dong-Hun Choi ◽  
Jeong-Kook Lee ◽  
Joon-Yong Cho
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Cognitive Function ◽  
Endurance Exercise ◽  
Mitochondrial Function ◽  
Treadmill Exercise ◽  
Tau Hyperphosphorylation ◽  
Positive Effect

PURPOSE: This study aimed to investigate the effect of 8 weeks of endurance exercise and MitoQ intake on tau hyperphosphorylation, oxidative stress, antioxidant modulating factors, mitochondrial function, and cognitive function in an AlCl3-induced Alzheimer’s disease animal model.METHODS: For the experimental animals, 40 mg/kg of aluminum chloride (AlCl3) was diluted with physiological saline for 60 days and intraperitoneally injected to create an Alzheimer’s disease animal model. In addition, endurance exercise was performed at a speed of 12 m/min using a treadmill for laboratory animals for 8 weeks, and MitoQ was applied with a 100 μm concentration of negative water. The rats were randomly divided into five groups: a saline control group (NC, n=6), an AlCl3 injection group (AC, n=6), an AlCl3 injection and treadmill exercise group (AE, n=6), an AlCl3 injection and MitoQ group (AM, n=6), and an AlCl3 injection and treadmill exercise and MitoQ intake group (AEM, n=6). The SPSS program was used for statistical analyses. Differences between the groups in each variable were analyzed using the one-way ANOVA.RESULTS: Endurance exercise and MitoQ intake for 8 weeks showed positive results in cognitive function and decreased tau hyperphosphorylation in the animal model with Alzheimer’s disease. In addition, they reduced oxidative stress (4-HNE, MDA) and had a positive effect on antioxidant indicators (catalase, SOD-1, SOD-2). Finally, they exhibited a positive effect on factors related to mitochondrial function (PGC-1, Tfam).CONCLUSIONS: Eight weeks of endurance exercise and MitoQ intake are thought to have a positive effect in alleviating Alzheimer’s disease in terms of improving cognitive function through AlCl3 accumulation, tau hyperphosphorylation, oxidative stress, antioxidant modulating factors, and mitochondrial function.

scholarly journals Exercise-Induced Benefits for Alzheimer’s Disease by Stimulating Mitophagy and Improving Mitochondrial Function

2021 ◽  
Vol 13 ◽  
Author(s):  
Jiling Liang ◽  
Cenyi Wang ◽  
Hu Zhang ◽  
Jielun Huang ◽  
Juying Xie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Early Stage ◽  
Memory Loss ◽  
Later Life ◽  
Cognitive Capacity ◽  
Neurodegenerative Process

Neurons are highly specialized post-mitotic cells that are inherently dependent on mitochondria due to their higher bioenergetic demand. Mitochondrial dysfunction is closely associated with a variety of aging-related neurological disorders, such as Alzheimer’s disease (AD), and the accumulation of dysfunctional and superfluous mitochondria has been reported as an early stage that significantly facilitates the progression of AD. Mitochondrial damage causes bioenergetic deficiency, intracellular calcium imbalance and oxidative stress, thereby aggravating β-amyloid (Aβ) accumulation and Tau hyperphosphorylation, and further leading to cognitive decline and memory loss. Although there is an intricate parallel relationship between mitochondrial dysfunction and AD, their triggering factors, such as Aβ aggregation and hyperphosphorylated Tau protein and action time, are still unclear. Moreover, many studies have confirmed abnormal mitochondrial biosynthesis, dynamics and functions will present once the mitochondrial quality control is impaired, thus leading to aggravated AD pathological changes. Accumulating evidence shows beneficial effects of appropriate exercise on improved mitophagy and mitochondrial function to promote mitochondrial plasticity, reduce oxidative stress, enhance cognitive capacity and reduce the risks of cognitive impairment and dementia in later life. Therefore, stimulating mitophagy and optimizing mitochondrial function through exercise may forestall the neurodegenerative process of AD.

scholarly journals Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer’s Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Yanan Sun ◽  
Cao Ma ◽  
Hui Sun ◽  
Huan Wang ◽  
Wei Peng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Metabolic Disease ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Diabetic Patients ◽  
Increased Risk ◽  
Impaired Insulin ◽  
The Brain

As a chronic metabolic disease, diabetes mellitus (DM) is broadly characterized by elevated levels of blood glucose. Novel epidemiological studies demonstrate that some diabetic patients have an increased risk of developing dementia compared with healthy individuals. Alzheimer’s disease (AD) is the most frequent cause of dementia and leads to major progressive deficits in memory and cognitive function. Multiple studies have identified an increased risk for AD in some diabetic populations, but it is still unclear which diabetic patients will develop dementia and which biological characteristics can predict cognitive decline. Although few mechanistic metabolic studies have shown clear pathophysiological links between DM and AD, there are several plausible ways this may occur. Since AD has many characteristics in common with impaired insulin signaling pathways, AD can be regarded as a metabolic disease. We conclude from the published literature that the body’s diabetic status under certain circumstances such as metabolic abnormalities can increase the incidence of AD by affecting glucose transport to the brain and reducing glucose metabolism. Furthermore, due to its plentiful lipid content and high energy requirement, the brain’s metabolism places great demands on mitochondria. Thus, the brain may be more susceptible to oxidative damage than the rest of the body. Emerging evidence suggests that both oxidative stress and mitochondrial dysfunction are related to amyloid-β (Aβ) pathology. Protein changes in the unfolded protein response or endoplasmic reticulum stress can regulate Aβ production and are closely associated with tau protein pathology. Altogether, metabolic disorders including glucose/lipid metabolism, oxidative stress, mitochondrial dysfunction, and protein changes caused by DM are associated with an impaired insulin signal pathway. These metabolic factors could increase the prevalence of AD in diabetic patients via the promotion of Aβ pathology.

scholarly journals Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer’s disease related pathology

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Amit U. Joshi ◽  
Lauren D. Van Wassenhove ◽  
Kelsey R. Logas ◽  
Paras S. Minhas ◽  
Katrin I. Andreasson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Alcohol Consumption ◽  
Mitochondrial Dysfunction ◽  
Aldehyde Dehydrogenase ◽  
Cortical Neurons ◽  
Aldehyde Dehydrogenase 2 ◽  
East Asians

AbstractAldehyde dehydrogenase 2 deficiency (ALDH2*2) causes facial flushing in response to alcohol consumption in approximately 560 million East Asians. Recent meta-analysis demonstrated the potential link between ALDH2*2 mutation and Alzheimer’s Disease (AD). Other studies have linked chronic alcohol consumption as a risk factor for AD. In the present study, we show that fibroblasts of an AD patient that also has an ALDH2*2 mutation or overexpression of ALDH2*2 in fibroblasts derived from AD patients harboring ApoE ε4 allele exhibited increased aldehydic load, oxidative stress, and increased mitochondrial dysfunction relative to healthy subjects and exposure to ethanol exacerbated these dysfunctions. In an in vivo model, daily exposure of WT mice to ethanol for 11 weeks resulted in mitochondrial dysfunction, oxidative stress and increased aldehyde levels in their brains and these pathologies were greater in ALDH2*2/*2 (homozygous) mice. Following chronic ethanol exposure, the levels of the AD-associated protein, amyloid-β, and neuroinflammation were higher in the brains of the ALDH2*2/*2 mice relative to WT. Cultured primary cortical neurons of ALDH2*2/*2 mice showed increased sensitivity to ethanol and there was a greater activation of their primary astrocytes relative to the responses of neurons or astrocytes from the WT mice. Importantly, an activator of ALDH2 and ALDH2*2, Alda-1, blunted the ethanol-induced increases in Aβ, and the neuroinflammation in vitro and in vivo. These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to AD associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation.

scholarly journals Cellular Senescence and Iron Dyshomeostasis in Alzheimer’s Disease

2019 ◽  
Vol 12 (2) ◽  
pp. 93 ◽  
Author(s):  
Shashank Masaldan ◽  
Abdel Ali Belaidi ◽  
Scott Ayton ◽  
Ashley I. Bush
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hydroxyl Radicals ◽  
Iron Accumulation ◽  
Brain Iron ◽  
Dependent Cell ◽  
Cellular Dysfunction ◽  
The Impact ◽  
The Brain

Iron dyshomeostasis is a feature of Alzheimer’s disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). However, the source of iron accumulation in pathologically relevant regions of the brain and its contribution to AD remains unclear. One likely contributor to iron accumulation is the age-associated increase in tissue-resident senescent cells that drive inflammation and contribute to various pathologies associated with advanced age. Iron accumulation predisposes ageing tissue to oxidative stress that can lead to cellular dysfunction and to iron-dependent cell death modalities (e.g., ferroptosis). Further, elevated brain iron is associated with the progression of AD and cognitive decline. Elevated brain iron presents a feature of AD that may be modified pharmacologically to mitigate the effects of age/senescence-associated iron dyshomeostasis and improve disease outcome.

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