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Increasing evidence demonstrated that mitophagy and endoplasmic reticulum stress (ERS) was closely associated with memory decline in elderly type 2 diabetes mellitus (T2DM). Tea polyphenols (TP), an excellent natural antioxidant, has been reported to have neuroprotective properties in aging and diabetes, but the underlying mechanisms are still not fully understood. This study targets ERS-mitophagy in hippocampal neurons to investigate the improvement effect of memory in aged T2DM rats by TP. Rats were randomly divided into the control group, the aged group, the aged T2DM model group, the TP 75, 150, 300 mg/kg groups. TP 300 mg/kg ameliorated mitophagy by decreasing the levels of p-mTOR (S2448), P62 and HSP60 and increasing the levels of PINK1 and Parkin, the ratio of LC3Ⅱ/LC3Ⅰ, co-localization of LC3 and HSP60 and the number of autophagosomes and autolysosomes. TP 300 mg/kg attenuated ERS by downregulating the levels of p-PERK, p-eIF2α, ATF4, GRP78 and restoring the ER structure. To further verify epigallocatechin gallate (EGCG), which is the main active component of TP, enhanced mitophagy by inhibiting ERS, PC12 cells were pretreated with ERS activator tunicamycin (TM) or ERS inhibitor 4-phenylbutyric acid (4-PBA). The results showed that the improvement of mitophagy by EGCG was inhibited by TM and promoted by 4-PBA. Collectively, ERS-mitophagy in hippocampal neurons plays a key role in the improvement of memory by TP in aged T2DM rats. This study will provide a new perspective and strategy for the prevention of memory decline in elderly with T2DM. [Display omitted] • Tea polyphenols improves spatial memory and apoptosis in hippocampal neurons. • Mitophagy and endoplasmic reticulum stress involve in the apoptosis. • Endoplasmic reticulum stress mediated by PERK/eIF2α/ATF4 signaling pathway. • Mitophagy mediated by mTOR/PINK1/Parkin signaling pathway. • Tea polyphenols improves mitophagy by inhibiting endoplasmic reticulum stress. [ABSTRACT FROM AUTHOR]

Many studies have examined the beneficial effects of tea polyphenols (TP) and proanthocyanidins (PC) on the memory impairment in different animal models. However, the combined effects of them on synaptic, memory dysfunction and molecular mechanisms have been poorly studied, especially in the menopause-related memory decline in rats. In this rat study, TP and PC were used to investigate their protective effects on memory decline caused by inflammation. We characterized the learning and memory abilities, synaptic plasticity, AMPAR, phosphorylation of the p38 protein, TNF-ɑ, structural synaptic plasticity-related indicators in the hippocampus. The results showed that deficits of learning and memory in OVX + D-gal rats, which was accompanied by dendrites and synaptic morphology damage, and increased expression of Aβ1-42 and inflammation. The beneficial effects of TP and PC treatment were found to prevent memory loss and significantly improve synaptic structure and functional plasticity. TP+PC combination shows more obvious advantages than intervention alone. TP and PC treatment improved behavioral performance, the hippocampal LTP damage and the shape and number of dendrites, dendritic spines and synapses, reduced the burden of Aβ and decreased the inflammation in hippocampus. In addition, TP and PC treatment decreased the expressions of Iba-1, TNF-α, TNFR1, and TRAF2. These results provided a novel evidence TP combined with PC inhibits p38 MAPK pathway, suppresses the inflammation in hippocampus, and increase the externalization of AMPAR, which may be one of the mechanisms to improve synaptic plasticity and memory in the menopause-related memory decline rats. [ABSTRACT FROM AUTHOR]

Tea is a rich source of pharmacologically active molecules that has been suggested to provide a variety of health benefits. However, its mechanism of action in aging-related intestinal flora dysbiosis mediated neuroinflammation is still unclear. This study aimed to explore whether tea polyphenols (TP) can improve memory by regulating intestinal flora mediated neuroinflammation in aging model rats. Ovariectomy (OVX) combined with D-galactose injection was used to establish aging rats related to menopause. The rats were divided into Sham control group, Aging model group, TP 75 mg/kg, 150 mg/kg, 300 mg/kg groups and VE group. After 12 weeks of intervention, the shuttle box test and Y maze test were used to check the memory of rats. The composition of intestinal flora was assessed by 16S rRNA sequencing technology. HE staining and ELISA were used to detect intestinal epithelial morphology and permeability, respectively. TLR4/NF-κB inflammation pathway related indicators were investigated by western blot, and the microglia activation in rat hippocampal tissue was checked by immunofluorescence. In the shuttle box test and the Y maze test, compared with the Sham control group, the memory of Aging model rats was significantly declined. It was observed that the intestinal flora of Aging model rats was dysbiosis, the permeability of the intestinal epithelium was increased. Further experimental results showed that the expression of TLR4/NF-κB inflammatory pathway related proteins in the hippocampus were increased, and the excessive activation of microglia was observed. The beneficial effects of TP intervention have been found to prevent memory decline and significantly improve brain inflammation induced by intestinal flora dysbiosis, and TP 300 mg/kg showed a more obvious advantage than TP 75 mg/kg. TP 300 mg/kg can significantly improve the behavior of rats, improve the composition and diversity of the intestinal flora, and the shape and function of the intestinal epithelium. By reversing the increased expression levels of TLR4, IRAK, p-IκBα and nuclear NF-κB p65 proteins in the hippocampus of Aging model rats, the activation of microglia in the CA1, CA3 and Dentate gyrus (DG) sub-regions of the hippocampus can be inhibited. TP inhibits the brain TLR4/NF-κB inflammatory signal pathway caused by the dysbiosis of intestinal flora, which may be one of the mechanisms to improve the memory decline in aging model rats. [Display omitted] • In this study, ovariectomy and D-galactose injection were used to establish aging model rats related to menopause. • The composition of the intestinal flora of aging rats was dysbiosis, which in turn triggered inflammation in the brain. • This study can provide laboratory evidence for the prevention of menopause-related memory decline. [ABSTRACT FROM AUTHOR]