Cornel iridoid glycoside protects against STAT1‐dependent synapse and memory deficits by increasing NMDA receptor expression in tau transgenic mice

Abstract Background P301S transgenic mice is an animal model of tauopathy and Alzheimer’s disease (AD), exhibiting tau pathology and synaptic dysfunction. Cornel iridoid glycoside (CIG) is an active ingredient extracted from Cornus officinalis , a traditional Chinese herb. The purpose of the present study was to investigate the effects and mechanisms of CIG on tau pathology and synaptic dysfunction using P301S mice. Method Intragastric administration of CIG for 3.5 months was applied to P301S mice from 9‐month‐old to 12.5‐month‐old of age. Objective recognition test and Y maze task were used to test the cognitive impairments of P301S mice. Electrophysiological recording was applied to record long‐term potential. Transmission electron microscopy was used to investigate the the ultrastructure and number of synapse. Immunohistochemical staining was applied to detect tau phosphorylation. Western blotting was used to detect the expression levels of related proteins. Results Intragastric administration of CIG for 3.5 months improved learning and memory abilities, increased the survival rate of P301S mice. Electrophysiological recordings and transmission Electron microscopy study showed that CIG improved synaptic plasticity, increased the ultrastructure and number of synapse. Moreover, CIG increased the expression of N‐methyl‐D‐aspartate receptors (NMDARs) subunits GluN1, GluN2A and GluN2B, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptor (AMPAR) subunit GluA1. The major mechanism of CIG involved in the regulation of synaptic dysfunction was to inhibited the activation of Janus kinase‐2 (JAK2) /signal transducer and activator of transcription 1 (STAT1) signaling pathway and STAT1‐induced suppression of NMDAR expression. Conclusion Based on our findings, CIG might be a promising candidate for the prevention of tauopathy such as AD.