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TRPM2 dependence of ROS-induced NLRP3 activation in Alzheimer's disease
Malihe Aminzadeh1, Mehrdad Roghani2, Azadeh Sarfallah3
1Laboratory of Neuro-Organic Chemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, 13145-1365, Tehran, 1417614335, Iran.
Abstract:
Recent studies have shown that neuroinflammation plays an important role in Alzheimer's disease (AD). Microglial cells are responsible for the phagocytosis of Amyloid-β (Aβ). However, it has been demonstrated that in AD patients the efficiency of phagocytosis decreases due to proinflammatory cytokines, such as Interleukin-1β (IL-1β), which is produced through the activation of NLRP3 inflammasome. In this study, we aimed at deciphering the mechanism underlying the NLRP3 activation. The results showed that Aβ induces an increase in the level of reactive oxygen species (ROS). According to this study, ROS produced from both mitochondria and NADPH oxidase was responsible for NLRP3 activation. In addition, it was observed that this high level of ROS activated the transient receptor potential melastatin 2 (TRPM2) channel, which causes an increase in the level of intracellular calcium. The results demonstrated that in the absence of intracellular calcium, caspase-1 cannot be activated and therefore the level of IL-1β decreases. Altogether, our findings supported the role of TRPM2 channel in ROS-induced NLRP3 activation in microglial cells through the exposure to Aβ.
Insights
Amyloid-β triggers neuroinflammation in Alzheimer's disease by activating the NLRP3 inflammasome in microglial cells. This process involves reactive oxygen species and the TRPM2 channel, leading to increased Interleukin-1β production.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Neuroinflammation is a key factor in Alzheimer's disease (AD) pathogenesis.
- Microglial phagocytosis of Amyloid-β (Aβ) is impaired in AD due to proinflammatory cytokines like Interleukin-1β (IL-1β).
- IL-1β production is mediated by the activation of the NLRP3 inflammasome.
Purpose of the Study:
- To elucidate the mechanism of NLRP3 inflammasome activation in microglial cells upon Aβ exposure.
- To investigate the role of reactive oxygen species (ROS) and calcium signaling in this process.
Main Methods:
- Investigated Aβ-induced ROS production in microglial cells.
- Assessed the involvement of mitochondrial and NADPH oxidase-derived ROS in NLRP3 activation.
- Examined the role of the TRPM2 channel and intracellular calcium in the signaling pathway.
- Measured caspase-1 activation and IL-1β levels under different conditions.
Main Results:
- Aβ exposure increased ROS levels in microglial cells.
- Both mitochondrial and NADPH oxidase contributed to Aβ-induced ROS production, activating NLRP3.
- Elevated ROS activated the TRPM2 channel, leading to increased intracellular calcium.
- The absence of intracellular calcium prevented caspase-1 activation and reduced IL-1β levels.
Conclusions:
- The TRPM2 channel is crucial for ROS-induced NLRP3 activation in microglial cells exposed to Aβ.
- This pathway highlights a novel mechanism linking Aβ, ROS, calcium, and neuroinflammation in Alzheimer's disease.
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