Syringaldehyde Ameliorates Cognitive Dysfunction in APP/PS1 Mice by Stabilizing the NLRP3 Pathway

This study aimed to assess the therapeutic efficacy of syringaldehyde (SYD) in Alzheimer's disease (AD) and to investigate its potential underlying molecular mechanisms. The potential of SYD for AD treatment was first explored through a network pharmacology approach. APPswe/PS1dE9 (APP/PS1) transgenic mice were treated with SYD via intraperitoneal injection for 9 weeks, and cognitive and behavioral functions were evaluated using the Y-maze, Morris water maze, and novel object recognition tests. Histopathological analysis was conducted to assess neuronal changes and amyloid plaque deposition in the hippocampus using immunofluorescence, hematoxylin and eosin staining, Nissl staining, and Congo red staining. RNA Sequencing and transcription factor prediction analyses were utilized to identify the potential molecular mechanisms underlying SYD's therapeutic effects. In addition, in vitro experiments were performed on HT22 hippocampal neuronal cells, including ROS assay, TUNEL assay, and quantitative Reverse transcription PCR, to validate the mechanisms suggested by the in vivo results. The results demonstrated that SYD treatment significantly reduced amyloid plaque deposition in the hippocampus of APP/PS1 mice, promoted neuronal repair, and improved cognitive performance. Further analysis indicated that these therapeutic effects were mediated by SYD's ability to enhance resistance to oxidative stress, alleviate neuronal damage, and inhibit the NF-κB/IL-1β/NLRP3 inflammatory pathway, thereby counteracting neuroinflammation induced by neuronal activation. In conclusion, this study provides strong evidence for the potential of SYD to ameliorate cognitive impairment and reduce amyloid plaque deposition in AD, highlighting its promising role as a therapeutic agent in the treatment of Alzheimer's disease.

Alzheimer’s disease; NF-κB; NLRP3; Oxidative stress; Syringaldehyde.