Tea Polyphenol Modulates Mitochondria‐Associated Endoplasmic Reticulum Membrane of Hippocampal Neurons Targeting Grp75 to Ameliorate Memory Impairment in the Aged <scp>T2DM</scp> Rats

Tea polyphenol (TP), as the most abundant and unique functional substance of tea, has been widely studied for the neuroprotective effects. Previous studies also found that TP improves the memory impairment of the aged T2DM rats, but the underlying molecular mechanism has not been fully clarified. The model of aged T2DM was induced by injecting D-galactose and STZ intraperitoneally, as well as feeding with a high-glucose-fat diet in rats, and D-galactose and D-glucose were used in PC12 cells. Memory function, mitochondrial damage, mitochondria-associated endoplasmic reticulum membrane (MAM), Ca²⁺, and apoptosis were detected to investigate the role of TP and its main functional component EGCG in the association between mitochondria and the endoplasmic reticulum. In addition, to further verify whether EGCG reduces apoptosis by regulating MAM, molecular docking and Grp75-siRNA were used. TP intervention alleviates memory impairment, improves insulin resistance, downregulates the expressions of the MAM-related proteins and MAM structure, and reduces apoptosis. Subsequently, EGCG intervention attenuates the interaction of MAM, as p-IP3R1-Grp75 and Grp75-VDAC1, and inhibits the mitochondrial Ca²⁺ level. In the experiments to validate the mechanism, the results showed that EGCG not only directly connects to Grp75 physically, but Grp75-siRNA combined with EGCG inhibits mitochondrial Ca²⁺ overload and cell apoptosis by regulating MAM. TP modulates MAM of hippocampal neurons targeting Grp75 to ameliorate memory impairment in the aged T2DM rats, which presents fresh molecular perspectives on the neuroprotective role of TP in T2DM-related memory impairment.