Syringin attenuates Alzheimer's disease-associated neuroinflammation by inhibiting NLRP3 inflammasome activation

NLRP3 inflammasome‑driven neuroinflammation contributes to Alzheimer's disease (AD), with the SWELL1 channel acting as a critical upstream signal. Syringin improved behavioral deficits in AD models, but its link to NLRP3 inhibition via SWELL1 remains unclear.

This study aimed to investigate how syringin ameliorates AD pathology by modulating microglial NLRP3 inflammasome activation and regulating the SWELL1 channel.

APP/PS1 mice (5 months) received daily syringin (20 or 60 mg/kg) or vehicle for 7 months. Morris water maze (MWM) and NLRP3 inflammasome markers were evaluated. BV2 microglial cells were used to assess syringin's effects on ATP‑induced activation, including inflammatory cytokine, NLRP3 inflammasome components, microglial phenotypes, and pyroptosis. Conditioned BV2 media were applied to HT22 neurons to assess neuroprotection. Interactions among inflammasome components, ASC oligomerization, and SWELL1 channel activity were further assessed. Molecular dynamics (MD) simulations were performed to predict syringin-SWELL1 protein binding.

In the MWM, syringin reduced escape latency. It also reduced inflammatory mRNA levels and decreased NLRP3, ASC, pro-caspase-1, and GSDMD-N protein levels. During activation, syringin suppressed cleaved caspase-1/IL-1β secretion, Iba-1 protein, transcription of microglial activation markers, LDH release, and GSDMD-N expression. Conditioned medium improved HT22 viability and reduced cleaved‑Caspase‑3. Syringin disrupted ASC-pro‑Caspase‑1 but not ASC-NLRP3 interaction, lowered ASC monomer/dimer, suppressed ROS, and restored mitochondrial potential. It inhibited SWELL1 currents. MD simulations suggested binding at key residues Tyr99 and Asp100.

Syringin may inhibit SWELL1 channel in microglia, thereby limiting NLRP3 inflammasome activation and reducing neuroinflammation in AD.