TLR4/Rac1/NLRP3 Pathway Mediates Amyloid-β-Induced Neuroinflammation in Alzheimer’s Disease

Abstract

Background: Neuroinflammation plays a crucial part in the initial onset and progression of Alzheimer’s disease (AD). NLRP3 inflammasome was demonstrated to get involved in amyloid-β (Aβ)-induced neuroinflammation. However, the mechanism of Aβ-triggered activation of NLRP3 inflammasome remains poorly understood. Objective: Based on our previous data, the study aimed to identify the downstream signals that bridge the activation of TLR4 and NLRP3 inflammasome associated with Aβ. Methods: BV-2 cells were transfected with TLR4siRNA or pretreated with a CLI-095 or NSC23766, followed by Aβ1–42 treatment. APP/PS1 mice were injected intraperitoneally with CLI-095 or NSC23766. NLRP3 inflammasome and microglia activation was detected with immunostaining and western blot. G-LISA and Rac1 pull-down activation test were performed to investigate the activation of Rac1. Real-time PCR and ELISA were used to detect the inflammatory cytokines. Aβ plaques were assessed by western blotting and immunofluorescence staining. Morris water maze test was conducted to determine the spatial memory in mice. Results: Rac1 and NLRP3 inflammasome were activated by Aβ in both in vitro and in vivo experiments. Inhibition of TLR4 reduced the activity of Rac1 and NLRP3 inflammasome induced by Aβ1–42. Furthermore, inhibition of Rac1 blocked NLRP3 inflammasome activation mediated by TLR4. Blocking the pathway by CLI095 or NSC23766 suppressed Aβ1–42-triggered activation of microglia, reduced the expression of pro-inflammatory mediators and ameliorated the cognition deficits in APP/PS1 mice. Conclusions: Our study demonstrated that TLR4/Rac1/NLRP3 pathway mediated Aβ-induced neuroinflammation, which unveiled a novel pathway and key contributors underlying the pathogenic mechanism of Aβ.