NDRG2 attenuates ischemia-induced astrocyte necroptosis via the repression of RIPK1

Zhu, Jie; Yang, Likun; Wang, Qiuhong; Lin, Wei; Yi, Feng; Xu, Ye-Ping; Chen, Wei‐Liang; Xiong, Kun; Wang, Yuhai

doi:10.3892/mmr.2020.11421

Cited by 15 publications

(14 citation statements)

References 38 publications

(49 reference statements)

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“…Expression of RIPK1, RIPK3, and MLKL were also increased in the neurons of old mice suggesting greater levels of necroptosis machinery in neurons with age. Our data are similar to reports of necroptosis in neurodegeneration where neurons were identified as the major cell type that express P-MLKL in the brains of patients with Alzheimer's disease [15], multiple sclerosis [53], Parkinson's disease [18], ischemic brain [73,74], and in Japanese encephalitis virus infection [75]. In the brains of patients with multiple sclerosis, microglia do not undergo necroptosis due to the lower expression of MLKL, whereas oligodendrocytes that have a higher expression of MLKL undergo necroptosis [21].…”

Section: Discussionsupporting

confidence: 91%

“…Whether a subpopulation of microglia undergo necroptosis or microglial necroptosis play a role in neuroinflammation in the aging brain needs to be investigated. Even though astrocytes are reported to undergo necroptosis in a mouse models of spinal cord injury and cerebral ischemia [73,74], we did not see any P-MLKL expression colocalize with GFAP-positive astrocytes from old mice. In the brains of AD patients, nearly 10% of total P-MLKL was observed to colocalize with GFAP-positive astrocytes.…”

Section: Discussioncontrasting

confidence: 82%

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Necroptosis increases with age in the brain and contributes to age-related neuroinflammation

Thadathil

Nicklas

Mohammed

et al. 2021

Preprint

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Chronic inflammation of the central nervous system (CNS), termed neuroinflammation, is a hallmark of aging and a proposed mediator of cognitive decline associated with aging. Neuroinflammation is characterized by the persistent activation of microglia, the innate immune cells of the CNS, with damage-associated molecular patterns (DAMPs) being one of the well-known activators of microglia. Because necroptosis is a cell death pathway that induce inflammation through the release of DAMPs, we hypothesized that an age-associated increase in necroptosis contributes to increased neuroinflammation with age. The marker of necroptosis, phosphorylated form of MLKL (P-MLKL), and kinases in the necroptosis pathway (RIPK1, RIPK3, and MLKL) showed a region-specific increase in the brain with age, specifically in the cortex layer V and the CA3 region of the hippocampus of mice. Similarly, MLKL-oligomers, which causes membrane binding and permeabilization were significantly increased in the cortex and hippocampus of old mice relative to young mice. Nearly 70 to 80% of P-MLKL immunoreactivity was localized to neurons and less than 10% was localized to microglia, whereas no P-MLKL was detected in astrocytes. P-MLKL expression in neurons was detected in the soma, not in the processes. Blocking necroptosis using Mlkl-/- mice reduced markers (Iba-1 and GFAP) of neuroinflammation in the brains of old mice and short-term treatment with the necroptosis inhibitor, necrostatin-1s, reduced expression of proinflammatory cytokines, IL-6 and IL-1β, in the hippocampus of old mice. Thus, our data demonstrate for the first time that brain necroptosis increases with age and contributes to age-related neuroinflammation in mice.

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Section: Discussionsupporting

confidence: 91%

Section: Discussioncontrasting

confidence: 82%

Necroptosis increases with age in the brain and contributes to age-related neuroinflammation

Thadathil

Nicklas

Mohammed

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Expressions of RIPK1, RIPK3, and MLKL were also increased in the neurons of old mice suggesting greater levels of necroptosis machinery in neurons with age. Our data are similar to reports of necroptosis in neurodegeneration where neurons were identified as the major cell type that express P-MLKL in the brains of patients with Alzheimer’s disease [ 15 ], multiple sclerosis [ 53 ], Parkinson’s disease [ 18 ], ischemic brain [ 73 , 74 ], and in Japanese encephalitis virus infection [ 75 ]. In the brains of patients with multiple sclerosis, microglia do not undergo necroptosis due to the lower expression of MLKL, whereas oligodendrocytes that have a higher expression of MLKL undergo necroptosis [ 21 ].…”

Section: Discussionsupporting

confidence: 90%

“…Whether a subpopulation of microglia undergo necroptosis or microglial necroptosis play a role in neuroinflammation in the aging brain needs to be investigated. Even though astrocytes are reported to undergo necroptosis in mouse models of spinal cord injury and cerebral ischemia [ 73 , 74 ], we did not see any P-MLKL expression co-localize with GFAP-positive astrocytes from old mice. In the brains of AD patients, nearly 10% of total P-MLKL was observed to colocalize with GFAP-positive astrocytes.…”

Section: Discussioncontrasting

confidence: 81%

Necroptosis increases with age in the brain and contributes to age-related neuroinflammation

et al. 2021

View full text Add to dashboard Cite

Chronic inflammation of the central nervous system (CNS), termed neuroinflammation, is a hallmark of aging and a proposed mediator of cognitive decline associated with aging. Neuroinflammation is characterized by the persistent activation of microglia, the innate immune cells of the CNS, with damage-associated molecular patterns (DAMPs) being one of the well-known activators of microglia. Because necroptosis is a cell death pathway that induces inflammation through the release of DAMPs, we hypothesized that an age-associated increase in necroptosis contributes to increased neuroinflammation with age. The marker of necroptosis, phosphorylated form of MLKL (P-MLKL), and kinases in the necroptosis pathway (RIPK1, RIPK3, and MLKL) showed a region-specific increase in the brain with age, specifically in the cortex layer V and the CA3 region of the hippocampus of mice. Similarly, MLKL-oligomers, which cause membrane binding and permeabilization, were significantly increased in the cortex and hippocampus of old mice relative to young mice. Nearly 70 to 80% of P-MLKL immunoreactivity was localized to neurons and less than 10% was localized to microglia, whereas no P-MLKL was detected in astrocytes. P-MLKL expression in neurons was detected in the soma, not in the processes. Blocking necroptosis using Mlkl−/− mice reduced markers of neuroinflammation (Iba-1 and GFAP) in the brains of old mice, and short-term treatment with the necroptosis inhibitor, necrostatin-1s, reduced expression of proinflammatory cytokines, IL-6 and IL-1β, in the hippocampus of old mice. Thus, our data demonstrate for the first time that brain necroptosis increases with age and contributes to age-related neuroinflammation in mice.

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“…It was confirmed in various neuronal cell models including immature or mature primary neuronal cell cultures [85][86][87][88][89][90], PC12 cells [88] or RGC-5 cells [91,92], although parameters of oxidative stress have not been measured in these studies. Apart from neurons, other cell types, such as astrocytes, oligodendrocytes or microglia cells could also be partially protected by Nec-1 against the OGD/R-evoked cell death [89,[93][94][95][96]. Moreover, DTIO (5-(3 ,5 -dimethoxybenzal)-2-thio-imidazole-4-ketone), an Nec-1 analog, has been protective against OGD/R-induced cell damage in cortical neurons, HT-22 cells and astrocytes [97].…”

Section: Neuroprotective Effects Of Necroptosis Inhibitors In In Vitro Ischemia/hypoxia Modelsmentioning

confidence: 99%

Preclinical Evidence for the Interplay between Oxidative Stress and RIP1-Dependent Cell Death in Neurodegeneration: State of the Art and Possible Therapeutic Implications

Jantas

Lasoń

2021

Antioxidants

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Neurodegenerative diseases are the most frequent chronic, age-associated neurological pathologies having a major impact on the patient’s quality of life. Despite a heavy medical, social and economic burden they pose, no causative treatment is available for these diseases. Among the important pathogenic factors contributing to neuronal loss during neurodegeneration is elevated oxidative stress resulting from a disturbed balance between endogenous prooxidant and antioxidant systems. For many years, it was thought that increased oxidative stress was a cause of neuronal cell death executed via an apoptotic mechanism. However, in recent years it has been postulated that rather programmed necrosis (necroptosis) is the key form of neuronal death in the course of neurodegenerative diseases. Such assumption was supported by biochemical and morphological features of the dying cells as well as by the fact that various necroptosis inhibitors were neuroprotective in cellular and animal models of neurodegenerative diseases. In this review, we discuss the relationship between oxidative stress and RIP1-dependent necroptosis and apoptosis in the context of the pathomechanism of neurodegenerative disorders. Based on the published data mainly from cellular models of neurodegeneration linking oxidative stress and necroptosis, we postulate that administration of multipotential neuroprotectants with antioxidant and antinecroptotic properties may constitute an efficient pharmacotherapeutic strategy for the treatment of neurodegenerative diseases.

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NDRG2 attenuates ischemia-induced astrocyte necroptosis via the repression of RIPK1

Cited by 15 publications

References 38 publications

Necroptosis increases with age in the brain and contributes to age-related neuroinflammation

Necroptosis increases with age in the brain and contributes to age-related neuroinflammation

Necroptosis increases with age in the brain and contributes to age-related neuroinflammation

Preclinical Evidence for the Interplay between Oxidative Stress and RIP1-Dependent Cell Death in Neurodegeneration: State of the Art and Possible Therapeutic Implications

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