NLRX1 Enhances Glutamate Uptake and Inhibits Glutamate Release by Astrocytes

Mahmoud, Shaimaa; Gharagozloo, Marjan; Simard, Camille; Amrani, Abdelaziz; Gris, Denis

doi:10.3390/cells8050400

Cited by 35 publications

(27 citation statements)

References 76 publications

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“…According to previous knowledge that 17β-estradiol can bind to its own receptor, ERα [48,49,50,51], we determined whether 17β-estradiol activate SIRT1 through ERα dependent and independent manner. Our Western blot and immunofluorescence results showed that d -gal treatment reduce ERα and SIRT1 expression in adult mouse brain (Figure 4a–c).…”

Section: Resultsmentioning

confidence: 99%

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17β-Estradiol Modulates SIRT1 and Halts Oxidative Stress-Mediated Cognitive Impairment in a Male Aging Mouse Model

Khan

Ullah

Rehman

et al. 2019

Cells

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Oxidative stress has been considered the main mediator in neurodegenerative disease and in normal aging processes. Several studies have reported that the accumulation of reactive oxygen species (ROS), elevated oxidative stress, and neuroinflammation result in cellular malfunction. These conditions lead to neuronal cell death in aging-related neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease. Chronic administration of d-galactose (d-gal) for a period of 10 weeks causes ROS generation and neuroinflammation, ultimately leading to cognitive impairment. In this study, we evaluated the estrogen receptor α (ERα)/silent mating type information regulation 2 homolog 1 (SIRT1)-dependent antioxidant efficacy of 17β-estradiol against d-gal-induced oxidative damage-mediated cognitive dysfunction in a male mouse model. The results indicate that 17β-estradiol, by stimulating ERα/SIRT1, halts d-gal-induced oxidative stress–mediated JNK/NF-ҡB overexpression, neuroinflammation and neuronal apoptosis. Moreover, 17β-estradiol ameliorated d-gal-induced AD-like pathophysiology, synaptic dysfunction and memory impairment in adult mouse brains. Interestingly, inhibition of SIRT1 with Ex527 (a potent and selective SIRT1 inhibitor) further enhanced d-gal-induced toxicity and abolished the beneficial effect of 17β-estradiol. Most importantly, for the first time, our molecular docking study reveals that 17β-estradiol allosterically increases the expression of SIRT1 and abolishes the inhibitory potential of d-ga. In summary, we can conclude that 17β-estradiol, in an ERα/SIRT1-dependent manner, abrogates d-gal-induced oxidative stress–mediated memory impairment, neuroinflammation, and neurodegeneration in adult mice.

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Section: Resultsmentioning

confidence: 99%

“…Previous studies demonstrated that 17β-estradiol can bind to its own receptor, ERα [48,49,50,51]. We determined whether 17β-estradiol can bind to its receptor and then activate SIRT1.…”

Section: Discussionmentioning

confidence: 99%

17β-Estradiol Modulates SIRT1 and Halts Oxidative Stress-Mediated Cognitive Impairment in a Male Aging Mouse Model

Khan

Ullah

Rehman

et al. 2019

Cells

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“…The assay was carried out as described by Shaimaa Mahmoud with slight modifications [ 28 ]. Astrocytes were seeded in a 24-well plate, and after treatments, the cells were washed 2 times with Hank's Balanced Salt Solution (HBSS) containing calcium and magnesium but without phenol (14025134, Gibco).…”

Section: Methodsmentioning

confidence: 99%

GLP-1 improves the supportive ability of astrocytes to neurons by promoting aerobic glycolysis in Alzheimer's disease

Zheng

Xie

Ren

et al. 2021

Molecular Metabolism

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Objective Astrocytes actively participate in energy metabolism in the brain, and astrocytic aerobic glycolysis disorder is associated with the pathology of Alzheimer's disease (AD). GLP-1 has been shown to improve cognition in AD; however, the mechanism remains unclear. The objectives of this study were to assess GLP-1's glycolytic regulation effects in AD and reveal its neuroprotective mechanisms. Methods The Morris water maze test was used to evaluate the effects of liraglutide (an analog of GLP-1) on the cognition of 4-month-old 5 FAD mice, and a proteomic analysis and Western blotting were used to assess the proteomic profile changes. We constructed an astrocytic model of AD by treating primary astrocytes with Aβ 1-42 . The levels of NAD+ and lactate were examined, and the oxidative levels were assessed by a Seahorse examination. Astrocyte-neuron co-culture was performed to evaluate the effects of GLP-1 on astrocytes’ neuronal support. Results GLP-1 improved cognition in 4-month-old 5 FAD mice by enhancing aerobic glycolysis and reducing oxidative phosphorylation (OXPHOS) levels and oxidative stress in the brain. GLP-1 also alleviated Aβ-induced glycolysis declines in astrocytes, which resulted in reduced OXPHOS levels and reactive oxygen species (ROS) production. The mechanism involved the activation of the PI3K/Akt pathway by GLP-1. Elevation in astrocytic glycolysis improved astrocyte cells’ support of neurons and promoted neuronal survival and axon growth. Conclusions Taken together, we revealed GLP-1's capacity to regulate astrocytic glycolysis, providing mechanistic insight into one of its neuroprotective roles in AD and support for the feasibility of energy regulation treatments for AD.

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“…Additionally, Glu entrance also increases the expression of GS, which would increase energy demands, and there-456 fore might promote GLUT-1 mediated glucose up-take 457 (Mendez-Flores et al, 2016;Mahmoud et al, 2019).…”

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confidence: 99%

Specific Deletion of the Astrocyte Leptin Receptor Induces Changes in Hippocampus Glutamate Metabolism, Synaptic Transmission and Plasticity

et al. 2020

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The aim of this study was to indentify the involvement of leptin receptors (LepR) in astrocytes in hippocampal synaptic transmission and plasticity and metabolism. To this end we used a genetic mouse model (GFAP-LepR À/À) of specific LepR ablation in GFAP positive cells and recorded excitatory postsynaptic potentials (fEPSPs) within the CA1 area. Glutamate (Glu) uptake and the expression of Glu transporters (EEAT3, GLT-1 and GLAST) and enzymes involved in Glu metabolism (glutamine synthase, GABA decarboxylase 65 and 67) were quantified. Modifications in the expression of GFAP, the glucose transporter (GLUT)-1, and the monocarboxylate transporters MCT-2 and MCT-4, were also analyzed. The results show that depletion of LepR in GFAP positive cells reduced basal synaptic transmission within the CA1 area and impaired N-methyl-D-aspartate (NMDA)evoked long-term depression (NMDA-LTD). Hippocampal slices from GFAP-LepR À/À mice displayed lower Glu uptake efficacy together with up-regulation of GLT-1, glutamine synthase, GFAP and GLUT-1. In conclusion, astrocyte LepRs are involved in the maintenance of Glu homeostasis and Glu neurotransmission within the hippocampus. Our findings support a role of hippocampal LepRs in synaptic plasticity, which could have an impact on memory and learning processes.

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NLRX1 Enhances Glutamate Uptake and Inhibits Glutamate Release by Astrocytes

Cited by 35 publications

References 76 publications

17β-Estradiol Modulates SIRT1 and Halts Oxidative Stress-Mediated Cognitive Impairment in a Male Aging Mouse Model

17β-Estradiol Modulates SIRT1 and Halts Oxidative Stress-Mediated Cognitive Impairment in a Male Aging Mouse Model

GLP-1 improves the supportive ability of astrocytes to neurons by promoting aerobic glycolysis in Alzheimer's disease

Specific Deletion of the Astrocyte Leptin Receptor Induces Changes in Hippocampus Glutamate Metabolism, Synaptic Transmission and Plasticity

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