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ObjectivesMethodsResultsDiscussionThe study aimed to explore whether TP could improve memory in the aged type 2 diabetic rat model by regulating microbiota-immune-synaptic plasticity axis.The experiment was divided into two parts. Firstly, to investigate the effects of TP on the physiopathology of the aged T2DM model rats, rats were randomly divided into the Normal control group, the aged group, the Aged T2DM model group, the TP 75, 150, 300 mg/kg groups, the 150 mg/kg Piracetam group and the 3 mg/kg Rosiglitazone group. Then, to further verify whether TP improved memory in aged T2DM rat model by regulating intestinal flora, the fecal microbiota transplantation (FMT) from the rats in the 300 mg/kg TP group into the rats in the aged T2DM model group was carried out. Effects on gut microbiota, colonic integrity (epithelial tight junction proteins), and endotoxemia (serum LPS) were examined, along with synaptic structure, synaptic plasticity-related structural proteins and inflammation signaling of the hippocampus in our study.Our results demonstrated that TP alleviated memory impairments in the aged T2DM rat model. The specific outcomes were as follows: TP 300 mg/kg corrected the gut dysbacteriosis, alleviated intestinal permeability reduction and peripheral/central inflammation, inhibited the TLR4/NF-κB signaling pathway. Meanwhile, TP improved the synaptic plasticity in the hippocampus of the aged T2DM model rats, whose expressions of SYN, PSD 95, NMDAR1 and GluR1 in hippocampus were significantly up-regulated. Surprisingly, rats of the FMT group displayed the same changes.TP improves the memory in aged T2DM rat model. The mechanism may be related to the alteration of gut flora, which can inhibit hippocampal TLR4/NF-κB signaling to attenuate neuroinflammation, then improve synaptic plasticity. The study proposes that TP interventions aimed at manipulating the gut microbiota may hold great potential as an effective approach for preventing and treating this disease. [ABSTRACT FROM AUTHOR]

[Display omitted] • This study revealed mechanisms of diabetes-related memory impairment in vivo and in vitro. • TP ameliorated memory impairment and neuronal apoptosis in aged T2DM rats. • TP improved hippocampal glucose uptake/metabolism and O-GlcNAc glycosylation/phosphorylation of Tau. • This study not only involves glycolysis and the TCA in glucose metabolism, but also focuses on the hexosamine biosynthesis pathway. • It provides new insights into the beneficial effect of TP on diabetes-related memory impairment. Diabetes mellitus (DM) plays a causative role in memory impairment. Neuroprotective effects of tea polyphenol (TP), a unique and vital functional component of tea, have been widely investigated in neurodegenerative diseases, but the exact mechanisms have still not been entirely clarified yet. Here, we conducted the experiment to assess whether TP could protect the aged T2DM rats from memory impairment and its potential mechanisms. Our study revealed that memory impairment in aged T2DM rats was alleviated after TP treatment. Both in vivo and in vitro experiments showed that TP raised expression of GLUT4, activities of key enzymes of glucose metabolism and production of ATP in the model group, along with elevated O-GlcNAc glycosylation and reduced phosphorylation of Tau. Collectively, TP ameliorates memory impairment in aged T2DM rats via modulating hippocampal glucose uptake/metabolism and O-GlcNAc glycosylation/phosphorylation of Tau, which provides new insights into the beneficial effect of TP on DM-related memory impairment. [ABSTRACT FROM AUTHOR]

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]