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Neuroinflammation-Modulating Agent SB1617 Enhances LC3-Associated Phagocytosis to Mitigate Tau Pathology
Hana Cho1, Bo Young Choi2,3, Young-Hee Shin4,5
1Department of Biophysics and Chemical Biology, Seoul National University, Seoul 08826, Korea.
Abstract:
Tau protein aggregation and propagation in neurons and surrounding microglia are well-known risk factors for neurodegenerative diseases. Therefore, emerging therapeutic strategies that target neuroinflammatory activity in microglia have the potential to prevent tauopathy. Here, we explored the microglia-mediated neuroprotective function of SB1617 against tau aggregation. Our study revealed that SB1617-inactivated pathogenic M1-like microglia, reduced the secretion of pro-inflammatory cytokines via translational regulation, and induced microglial polarization toward the M2 phenotype and phagocytic function. Furthermore, we observed that extracellular pathogenic tau aggregates were eliminated via LC3-associated phagocytosis. The in vivo efficacy of SB1617 was confirmed in mice with traumatic brain injury in which SB1617 exerted neuroprotective effects by reducing pathogenic tau levels through microglia-mediated anti-inflammatory activity. Our results indicated that SB1617-mediated microglial surveillance with LC3-associated phagocytosis is a critical molecular mechanism in the regulation of tau proteostasis. This study provides new insights into tauopathies and directions for developing novel therapies for neurodegenerative diseases.
Insights
SB1617 therapy reduces harmful tau protein buildup by reprogramming microglia, a key brain immune cell. This approach lessens neuroinflammation and promotes clearance of toxic tau aggregates, offering potential for treating neurodegenerative diseases like tauopathy.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Tau protein aggregation and spread are major drivers of neurodegenerative diseases.
- Microglia, the brain's immune cells, play a critical role in neuroinflammation and tauopathy.
- Targeting microglial activity presents a promising therapeutic avenue for tauopathies.
Purpose of the Study:
- To investigate the neuroprotective effects of SB1617 on tau aggregation.
- To elucidate the mechanisms underlying SB1617's action on microglia.
- To evaluate the therapeutic potential of SB1617 in a mouse model of brain injury.
Main Methods:
- Assessing SB1617's impact on microglial phenotype and cytokine secretion.
- Investigating tau aggregate clearance via LC3-associated phagocytosis.
- Evaluating SB1617's efficacy in a mouse model of traumatic brain injury.
Main Results:
- SB1617 inactivated M1-like microglia, reducing pro-inflammatory cytokine release.
- SB1617 promoted M2 microglial polarization and enhanced phagocytic activity.
- Extracellular tau aggregates were cleared through LC3-associated phagocytosis.
- SB1617 demonstrated neuroprotective effects in vivo by reducing tau levels.
Conclusions:
- SB1617 modulates microglial function to reduce neuroinflammation and promote tau clearance.
- LC3-associated phagocytosis is a key mechanism in SB1617-mediated tau proteostasis.
- SB1617 represents a potential therapeutic strategy for tauopathies and related neurodegenerative diseases.
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