Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by persistent neuroinflammation, oxidative imbalance, cognitive decline, Aβ buildup, tau phosphorylation, and synaptic dysfunction. Despite progress in understanding AD's development, effective treatments are still limited. Isorhapontigenin (ISO), a methoxylated stilbenoid similar to resveratrol, shows neuroprotective, anti-inflammatory, and antioxidative effects. In this study, we explored ISO's therapeutic potential in a mouse model of AD-like pathology induced by LPS, focusing on TLR4/RAGE-triggered NF-κB signaling pathway and related neuroinflammatory responses, oxidative stress, GSK3β signaling, tau pathology, Aβ accumulation, glial activation, and synaptic health. Western blot and immunofluorescence techniques were used to measure the levels of TLR4/RAGE signaling components, glial markers (GFAP and Iba-1), p-NF-κB signaling pathway activation, proinflammatory cytokines ( TNF-α, COX-2, and IL-1β), oxidative stress indicators (Nrf2 and HO-1), neurodegeneration markers (p-GSK3β, p-tau, and Aβ), and synaptic proteins (PSD-95, SNAP-23, and SYP). Nissl staining helped assess neuronal density and structure. BV2 microglial cells were treated similarly in vitro, followed by viability tests and Apotox-Glo™ triplex assays, along with protein expression analysis. The levels of TLR4, RAGE, GFAP, and Iba-1 increased in the LPS-treated group, along with proinflammatory mediators, ROS, LPO, and neurodegenerative markers. Yet, ISO treatment significantly reduced their expression. Moreover, LPS lowered Nrf2 and HO-1 levels, reduced p-GSK3β, and decreased synaptic proteins, indicating oxidative damage and synaptic failure. ISO reversed these changes by restoring p-GSK3β, activating Nrf2/HO-1, and boosting synaptic protein levels, followed by behavioral improvement as evidenced by reduced escape latency and increased spontaneous alternations in the Morris water maze (MWM) and Y-maze tests. Additionally, ISO preserved neuronal and synaptic integrity and provided consistent neuroprotection in BV2 cells. Overall, these results demonstrate that ISO reduces LPS-induced AD-like pathology by activating TLR4/RAGE-driven p-NF-κB, decreasing neuroinflammation, enhancing Nrf2/HO-1 activity, inhibiting GSK3β, lowering Aβ and p-Tau accumulation, preserving synaptic health, and prominent improvement in spatial memory, emphasizing its potential as an AD treatment.
