Microglial TAK1 promotes neurotoxic astrocytes and cognitive impairment in LPS-induced hippocampal neuroinflammation.

The peripheral immune system has a strong effect on the central nervous system (CNS). Systemic lipopolysaccharides (LPS) administration triggers robust microglial activation and induces significant inflammatory responses in the hippocampus. This study investigates the role of Transforming Growth Factor-β-Activated Kinase 1 (TAK1) in mediating LPS-induced hippocampal neuroinflammation and cognitive impairment. Our findings reveal that LPS induces activation of microglial TAK1, which in turn activates downstream effector NF-κB/p65 to release pro-inflammatory cytokines. The activated microglia also promote astrocytes to polarize into a neurotoxic phenotype (A1-like phenotype) and cause the loss of newborn neurons in the hippocampal dentate gyrus (DG). However, TAK1 reduction inhibits microglial responses, limits neurotoxic astrocytes, rescues newborn neurons, and subsequently improves LPS-induced cognitive deficits, suggesting that targeting TAK1 may be an effective strategy for alleviating neuroinflammation. The interaction between TAK1 activation, microglial responses, and the transition of neurotoxic astrocytes enhances our understanding of the cellular dynamics driving LPS-induced neuroinflammation, suggesting that TAK1 may be a therapeutic target for treating cognitive impairment.