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Synapse dysfunction is an early hallmark of Alzheimer’s disease (AD), and was considered to be closely related to memory loss. The molecular mechanisms that trigger synapse loss and dysfunction remain poorly understood. Increasing evidence shows a link between Rho GTPases and synapse plasticity. Rho GTPases play a role in controlling synapse function by regulating actin cytoskeleton and dendritic spines. Observations have suggested that phytochemicals, such as flavonoids, alleviate cognition impairment in AD. However, to date, the link between the protective effect of flavonoids on AD and the activity of Rho GTPases remains uninvestigated. In this study, APP/PS1 mice were used as an AD model, and we found that synapse loss occurred in AD mice brain. Flavonoids extracted from leaves of Diospyros kaki (FLDK) were used to investigate whether its protective effects on synapse were related to Rho GTPases activity in AD mice. The Rho GTPases Activation Kit showed that Ras homologous member A (RhoA)-GTP was significantly higher and Ras-related C3 botulinum toxin substrate 1 (Rac1)-GTP was significantly lower in APP/PS1 mice than in normal mice, and RhoA-GTP activity was significantly inhibited by FLDK. We also found that FLDK improved learning and memory function, and antagonized the downregulation expressions of synapse-related proteins such as synaptophysin and drebrin. These findings suggest that FLDK is a potential therapeutic agent for AD, and modulation of Rho GTPases activity might contribute toward its protective effect.