Du-Shu-Wan alleviates Tau protein phosphorylation in Alzheimer's disease by regulating MAPK/JNK signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is one of the leading causes of cognitive impairment and dementia among the elderly and has become an urgent public health challenge due to population ageing. Du-Shu-Wan (DSW) is an ancient Chinese herbal medicine that aims to enhance memory and soothe the spirit, and has long been applied for forgetfulness and cognitive decline. At present, there is still no systematic research on the pharmacological basis of DSW and its specific molecular mechanisms for alleviating AD. AIM OF THE STUDY: The researchers aimed to investigate the mechanisms by which DSW attenuates AD-related pathological changes in animal models and in vitro cultured cells. MATERIALS AND METHODS: The chemical composition of DSW was characterized using UPLC-Q-TOF-MS. Subsequently, HE staining, Nissl staining, and silver staining were employed to evaluate the effects of DSW on neuronal damage in an AD rat model induced by intracerebral injection of Aβ1-42 into the lateral ventricle. Potential mechanisms of action were investigated through network pharmacology, molecular docking, and transcriptomics. Finally, the results of the in vivo experiments were validated in an HT22 cell model. RESULTS: This study reports the identification of 101 compounds from DSW for the first time. After a four-week course of DSW treatment, AD model rats exhibited significantly improved cognitive function, along with decreased neuronal injury and reduced neurofibrillary tangle pathology. A comprehensive analysis suggests that DSW enhanced cognitive function, an effect associated with inhibition of the MAPK/JNK pathway and reduction in the level of phosphorylated Tau at Ser422 sites. Additionally, in vitro experiments further showed that the protective effect of DSW-containing serum against Aβ1-42-induced neurotoxicity was associated with reduced JNK activation, and this reversal was obviously compromised by a JNK activator. CONCLUSIONS: According to this study, DSW may enhance cognitive function in AD rats, an effect that is associated with reduced JNK pathway activity and reduced tau protein hyperphosphorylation at Ser422.