TRPM2 dependence of ROS-induced NLRP3 activation in Alzheimer's disease

Aminzadeh, Malihe; Roghani, Mehrdad; Sarfallah, Azadeh; Riazi, Gholamhossein

doi:10.1016/j.intimp.2017.10.024

Cited by 68 publications

(47 citation statements)

References 38 publications

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“…39 In a very recent Alzheimer's disease study, ROS induced DNA damage and rises in ADPR generation, which increased intracellular Ca 2þ to a level that induced NLRP3 activation in microglial cells. 40 It was suggested that in type 2 diabetes mellitus, TRPM2 channels are a potential target for alleviating NLRP3 inflammasome activation stemming from hyperglycemia-induced oxidative stress. 41 Our results suggest that the inflammatory conditions associated with some ocular surface diseases in some cases may stem from TRPM2 activation because the osmotic stress we imposed is comparable to the tear film osmolarity of clinical samples obtained from some individuals afflicted with DE disease.…”

Section: Discussionmentioning

confidence: 99%

Hyperosmotic Stress–Induced TRPM2 Channel Activation Stimulates NLRP3 Inflammasome Activity in Primary Human Corneal Epithelial Cells

Zheng

Tan

Ren

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of this study was to determine whether either a hyperosmotic or oxidative stress induces NLRP3 inflammasome activation and increases in bioactive IL-1b secretion through transient receptor potential melastatin 2 (TRPM2) activation in primary human corneal epithelial cells (PHCECs). METHODS.Real-time PCR, Western blots, and immunofluorescent staining were used to evaluate TRPM2 and NLRP3, ASC, caspase-1, and IL-1b mRNA and protein expression levels, respectively. A CCK-8 assay evaluated cell viability. Hyperosmotic 500 mOsm and oxidative 0.5 mM H 2 O 2 stresses were imposed. TRPM2 expression was inhibited with a TRPM2 inhibitor, 20 lM N-(p-amylcinnamoyl) anthranilic acid (ACA), or TRPM2 siRNA knockdown.RESULTS. In the hypertonic medium, TRPM2, NLRP3, ASC, caspase-1, and IL-1b gene and protein expression levels rose after 4 hours (P 0.043), whereas ACA preincubation suppressed these rises (P 0.044). Similarly, H 2 O 2 upregulated TRPM2 protein expression by 80%, and induced both NLRP3 inflammasome activation and increased bioactive IL-1b secretion (P 0.036), whereas ACA pretreatment suppressed these effects (P 0.029). TRPM2 siRNA transfection reduced TRPM2 gene expression by 70% (P ¼ 0.018) in this hyperosmotic medium and inhibited the increases in NLRP3, caspase-1, and IL-1b gene (P 0.028) and protein expression (P 0.037).CONCLUSIONS. TRPM2 activation by either a hyperosmotic or oxidative stress contributes to mediating increases in NLRP3 inflammasome activity and bioactive IL-1b expression because inhibiting TRPM2 activation or its expression blunted both of these responses in PHCECs. This association points to the possibility that TRPM2 is a viable target to suppress hyperosmotic-induced corneal epithelial inflammation.

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Section: Discussionmentioning

confidence: 99%

Hyperosmotic Stress–Induced TRPM2 Channel Activation Stimulates NLRP3 Inflammasome Activity in Primary Human Corneal Epithelial Cells

Zheng

Tan

Ren

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…Aggregated βA can reduce mitochondrial respiration in neurons and astrocytes via the inhibition of complexes I and IV . Inhibition of ETC potentially can induce ROS production, although a direct increase in mitochondrial ROS production was shown in some studies . However, superoxide production from mitochondria, but not from NADPH oxidase, was shown to be associated with blocked long‐term potentiation in a Tg2576 mouse model of AD .…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Role of mitochondrial ROS in the brain: from physiology to neurodegeneration

Angelova¹,

Abramov²

2018

FEBS Letters

603

402

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Edited by Wilhelm JustMitochondria are key cell organelles in that they are responsible for energy production and control many processes from signalling to cell death. The function of the mitochondrial electron transport chain is coupled with the production of reactive oxygen species (ROS) in the form of superoxide anion or hydrogen peroxide. As a result of the constant production of ROS, mitochondria are protected by highly efficient antioxidant systems. The rapidly changing levels of ROS in mitochondria, coupled with multiple essential cellular functions, make ROS apt for physiological signalling. Thus, mutations, environmental toxins and chronic ischaemic conditions could affect the mitochondrial redox balance and lead to the development of pathology. In long-living and non-mitotic cells such as neurons, oxidative stress induced by overproduction of mitochondrial ROS or impairment of the antioxidant defence results in a dysfunction of mitochondria and initiation of the cell death cascade. Mitochondrial ROS overproduction and changes in mitochondrial redox homeostasis have been shown to be involved in both a number of neurological conditions and a majority of neurodegenerative diseases. Here, we summarise the involvement of mitochondrial ROS in the mechanism of neuronal loss of major neurodegenerative disorders.

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“…There is accumulating evidence to show an important role of the TRPM2 channel in neurodegenerative diseases. Amyloid-β peptide-induced ROS generation-mediated activation of the TRPM2 channel results in synaptic loss and neuronal death in hippocampus, 38,41,55 microglial cell activation and generation of proinflammatory mediators 37,55,56 and impairments in the BBB and neurovascular function, 35 supporting a critical role of the TRPM2 channel in the pathogenesis of AD. 57…”

Section: Trpmchannel a S A Common Molecul Ar Mechanis M Mediating Rmentioning

confidence: 99%

“…There is compelling evidence from recent studies that supports an important role for the TRPM2 channel in mediating microglial cell activation and generation of proinflammatory mediators and neuroinflammation in response to stimulation of oxidative stress or stimuli that known to induce ROS generation such as amyloid-β peptides. 37,56,57 It has been also shown that TRPM2-mediated activation of microglial cells contributes to chronic cerebral hypo-perfusion brain damage 68 and activation of microglia and astrocytes in neonatal hypoxic-ischaemic brain damage. 69 It remains unknown regarding the role of TRPM2dependent microglial activation and neuroinflammation in ischaemia-reperfusion-induced delayed neuronal death.…”

Section: Trpm2 Channel In Neonatal Hyp Oxic-ischaemic B R Ain Damag Ementioning

confidence: 99%

TRPM2 channel: A novel target for alleviating ischaemia‐reperfusion, chronic cerebral hypo‐perfusion and neonatal hypoxic‐ischaemic brain damage

Mai

Mankoo

Wei

et al. 2019

J Cellular Molecular Medi

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The transient receptor potential melastatin‐related 2 (TRPM2) channel, a reactive oxygen species (ROS)‐sensitive cation channel, has been well recognized for being an important and common mechanism that confers the susceptibility to ROS‐induced cell death. An elevated level of ROS is a salient feature of ischaemia‐reperfusion, chronic cerebral hypo‐perfusion and neonatal hypoxia‐ischaemia. The TRPM2 channel is expressed in hippocampus, cortex and striatum, the brain regions that are critical for cognitive functions. In this review, we examine the recent studies that combine pharmacological and/or genetic interventions with using in vitro and in vivo models to demonstrate a crucial role of the TRPM2 channel in brain damage by ischaemia‐reperfusion, chronic cerebral hypo‐perfusion and neonatal hypoxic‐ischaemia. We also discuss the current understanding of the underlying TRPM2‐dependent cellular and molecular mechanisms. These new findings lead to the hypothesis of targeting the TRPM2 channel as a potential novel therapeutic strategy to alleviate brain damage and cognitive dysfunction caused by these conditions.

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TRPM2 dependence of ROS-induced NLRP3 activation in Alzheimer's disease

Cited by 68 publications

References 38 publications

Hyperosmotic Stress–Induced TRPM2 Channel Activation Stimulates NLRP3 Inflammasome Activity in Primary Human Corneal Epithelial Cells

Hyperosmotic Stress–Induced TRPM2 Channel Activation Stimulates NLRP3 Inflammasome Activity in Primary Human Corneal Epithelial Cells

Role of mitochondrial ROS in the brain: from physiology to neurodegeneration

TRPM2 channel: A novel target for alleviating ischaemia‐reperfusion, chronic cerebral hypo‐perfusion and neonatal hypoxic‐ischaemic brain damage

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