Ferulic acid ameliorates neuroinflammation and cognitive deficits in Alzheimer’s disease via the mGluR5/CaMKII/NF-κB pathway

Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which neuroinflammation plays a critical pathogenic role. Ferulic acid (FA), a natural phenolic compound widely distributed in plants, has been increasingly reported to exert potent neuroprotective effects. However, the specific molecular mechanism underlying the neuroprotective effects of FA in AD remains unclear, which limits its further development and application as a potential therapeutic agent for AD. Objectives The present study aimed to investigate the therapeutic effects of FA on AD and clarify its underlying molecular mechanism, focusing on the mGluR5/CaMKII/NF-κB pathway and its association with microglia-mediated neuroinflammation. Methods 3×Tg-AD mice and LPS-induced BV2 cells were used as experimental models to explore the effects of FA. Multiple experimental techniques were employed for comprehensive analyses, including immunofluorescence, flow cytometry, Nissl staining, HE staining, and western blot. These methods were used to detect mGluR5/CaMKII/NF-κB pathway protein levels, inflammatory factor formation, microglial activation, and pathological changes in AD models. Results In 3×Tg-AD mice, FA treatment significantly increased the protein level of mGluR5, ameliorated neuroinflammation, and reduced Aβ plaque deposition in the brain as well as p-tau levels in the plasma. In LPS-stimulated BV2 cells, FA treatment decreased the formation of the pro-inflammatory factors and alleviated the over-activation of microglia. Further analyses confirmed that FA-induced up-regulation of mGluR5 inhibited the CaMKII/NF-κB signaling cascade, which in turn suppressed neuroinflammation and ameliorated cognitive deficits. Conclusion These results demonstrated that FA exerts neuroprotective effects in AD as a specific mGluR5 agonist. The underlying mechanism is related to the regulation of the mGluR5/CaMKII/NF-κB pathway, which suppresses microglia-mediated neuroinflammation and ultimately ameliorates cognitive impairment. This study provides novel insights into the molecular mechanism of FA in AD treatment and highlights its promising potential as a candidate therapeutic agent for AD.