Cornel Iridoid Glycoside Protects Against STAT1-Dependent Synapse and Memory Deficits by Increasing N-Methyl-D-aspartate Receptor Expression in a Tau Transgenic Mice.

Denglei Ma,Weipeng Wei,Rui Huang,Lan Zhang,Kaiwen Guo,Zirun Zhao,Lin Li,Lihong Gu

doi:10.3389/fnagi.2021.671206

Abstract

P301S transgenic mice are 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. In the present study, the purpose was to investigate the effects and mechanisms of CIG on tau pathology and synaptic dysfunction using P301S transgenic mice. The results showed that intragastric administration of CIG for 3.5 months improved cognitive impairments and the survival rate of P301S mice. Electrophysiological recordings and transmission electron microscopy study showed that CIG improved synaptic plasticity and increased the ultrastructure and number of synapse. Moreover, CIG increased the expression levels of N-methyl-D-aspartate receptors (NMDAR) subunits GluN1, GluN2A, and GluN2B, and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit GluA1. We inferred that the major mechanism of CIG involving in the regulation of synaptic dysfunctions was inhibiting the activation of Janus kinase-2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) signaling pathway and alleviating STAT1-induced suppression of NMDAR expressions. Based on our findings, we thought CIG might be a promising candidate for the therapy of tauopathy such as AD.

Highlights

Alzheimer’s disease (AD) is a common neurodegenerative disease characterized by progressive dementia and results in an enormous emotional and financial burden in the patients and society worldwide (Jia et al, 2020)
The present study showed that the percentages of alternation behavior in Y maze of P301S Tg mice were remarkably lower than those in nTg mice (P < 0.05; Figure 1B), and Cornel iridoid glycoside (CIG) treatment at 100 and 200 mg/kg increased the percentages of alternation behavior of P301S mice (P < 0.05; Figure 1B)
These results indicated that CIG ameliorated the non-spatial and spatial cognitive impairments in P301S Tg mice

Summary

Introduction

Alzheimer’s disease (AD) is a common neurodegenerative disease characterized by progressive dementia and results in an enormous emotional and financial burden in the patients and society worldwide (Jia et al, 2020). Rescue of synaptic and neuronal connectivity loss by inhibition of tau pathology is reported as the most promising treatment for tauopathies, such as AD (Iqbal et al, 2018). Filamentous tau lesions began to develop in P301S mice since 6 months of age and progressively accumulated in association with neuronal loss at 9–12 months of age (Yoshiyama et al, 2007). In vivo measurement of glutamate loss is reported to be in association with synapse loss and synaptic dysfunction in P301S mice (Crescenzi et al, 2014). These results showed that synaptic pathology might be one of the earliest neurotoxic consequences of pathogenic human tau expression in animal models of tauopathy

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Conclusion