Neuroinflammation-Modulating Agent SB1617 Enhances LC3-Associated Phagocytosis to Mitigate Tau Pathology

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.

Automated summary

In this study, we investigated the neuroprotective function of SB1617 against tau aggregation mediated by microglia. Our findings showed that SB1617 deactivated pathogenic M1-like microglia, reduced the secretion of pro-inflammatory cytokines, induced microglial polarization towards the M2 phenotype, and enhanced phagocytic function. In addition, we observed the clearance of extracellular pathogenic tau aggregates through LC3-associated phagocytosis. Furthermore, in vivo experiments confirmed the neuroprotective effects of SB1617 in a mouse model of traumatic brain injury by reducing pathogenic tau levels through microglia-mediated anti-inflammatory activity. Our results indicate that SB1617-mediated microglial surveillance with LC3-associated phagocytosis is a critical molecular mechanism in the regulation of tau proteostasis.