Epigallocatechin-3-gallate attenuates impairment of learning and memory in chronic unpredictable mild stress-treated rats by restoring hippocampal autophagic flux.

Hong-Feng Gu,Kai-Quan Jing,Qiao-Zhen Tong,Ya-Xiong Nie,Ya-Ling Tang,Xi-Long Zheng,Yang Zeng,Duan-Fang Liao,Jianhua Zhang

doi:10.1371/journal.pone.0112683

Abstract

Epigallocatechin gallate (EGCG) is a major polyphenol in green tea with beneficial effects on the impairment in learning and memory. Autophagy is a cellular process that protects neurons from stressful conditions. The present study was designed to investigate whether EGCG can rescue chronic unpredictable mild stress (CUMS)-induced cognitive impairment in rats and whether its protective effect involves improvement of autophagic flux. As expected, our results showed that CUMS significantly impaired memory performance and inhibited autophagic flux as indicated by elevated LC3-II and p62 protein levels. At the same time, we observed an increased neuronal loss and activated mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6k) signaling in the CA1 regions. Interestingly, chronic treatment with EGCG (25 mg/kg, i.p.) significantly improved those behavioral alterations, attenuated histopathological abnormalities in hippocampal CA1 regions, reduced amyloid beta1–42 (Aβ1−42) levels, and restored autophagic flux. However, blocking autophagic flux with chloroquine, an inhibitor of autophagic flux, reversed these effects of EGCG. Taken together, these findings suggest that the impaired autophagy in CA1 regions of CUMS rats may contribute to learning and memory impairment. Therefore, we conclude that EGCG attenuation of CUMS-induced learning and memory impairment may be through rescuing autophagic flux.

Highlights

Accumulating evidence suggests that chronic unpredictable mild stress (CUMS) is a significant etiological factor for neurodegenerative disorders characterized by amyloid-b (Ab) deposition [1], neuron loss [2], learning and memory deficits [3,4]
Our major findings include: (1) CUMS resulted in increased intracellular Ab1242 accumulation, cells loss, and autophagic flux impairment in CA1 of rats; (2) Epigallocatechin gallate (EGCG)-treatment efficiently ameliorated learning and memory deficits, and autophagic flux impairment induced by CUMS; (3) EGCG rescue of the autophagic influx may be through inhibition of mammalian target of rapamycin (mTOR) signaling pathway
These results suggested that EGCG may be exploited as a potential therapeutic reagent for the treatment of learning and memory deficits associated with abnormal autophagy

Summary

Introduction

Accumulating evidence suggests that chronic unpredictable mild stress (CUMS) is a significant etiological factor for neurodegenerative disorders characterized by amyloid-b (Ab) deposition [1], neuron loss [2], learning and memory deficits [3,4]. In humans and animals, the offspring of mothers that experience stress during pregnancy have been reported to display cognitive dysfunctions [6]. These findings suggest that chronic stress plays a critical role in the development of learning and memory impairment. The majority of present studies examining stress contributions to learning and memory deficits have focused on HPA dysfunction, tau phosphorylation and Ab aggregation in AD transgenic mice [1,2,4], and only few studies have focused on the role of autophagy in stress-induced memory impairment. Autophagy is a highly regulated process characterized by the formation of double or multi-membrane vesicles (autophagosomes) that sequester portions of cytosol

Methods

Results

Conclusion