TLR2 regulation of NF-κB and NLRP3-driven pyroptosis in Alzheimer's disease.

Although upregulation of toll-like receptor 2 (TLR2) excessively activates pro-inflammatory microglia through Aβ peptides, it remains unclear whether TLR2 regulates neuronal pyroptosis via the NF-κB/NLRP3 pathway in Alzheimer's disease (AD). We assessed TLR2 expression in peripheral blood from clinical samples and employed SH-SY5Y cells for initial screening. AD pathology was simulated by Aβ1-42 stimulation, and pathway regulatory relationships were dissected through TLR2 knockdown, NF-κB overexpression, and NLRP3 activation experiments. APP/PS1 mice were treated with sh-TLR2. Results demonstrated that high TLR2 expression activated the NF-κB/NLRP3 pathway and promoted pyroptosis, while TLR2 silencing suppressed Aβ1-42-driven pyroptosis in SH-SY5Y cells by inhibiting this pathway. NF-κB overexpression or NLRP3 activation partially reversed the protective effect of TLR2 silencing. In vivo experiments confirmed the role of TLR2 knockdown in AD mice. Thus, this study revealed that TLR2 drives neuronal pyroptosis via the NF-κB/NLRP3 pathway, providing a novel therapeutic target for AD. These findings complement existing microglia-centered TLR2 research and broadens the understanding of neuroinflammatory regulation. However, SH-SY5Y cells differ from primary neurons in maturity, which may limit mechanistic extrapolation. Further validation in induced pluripotent stem cells-derived primary neurons or humanized mouse models will enhance the clinical translational potential of these findings.