Abstract：
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.
摘要：
越来越多的证据表明，线粒体自噬和内质网应激（ERS）与老年2型糖尿病（T2DM）的记忆力下降密切相关。茶多酚(TP),一种极好的天然抗氧化剂,据报道，在衰老和糖尿病中具有神经保护特性，但是潜在的机制仍然没有完全理解。本研究以海马神经元ERS-线粒体自噬为目标，探讨TP对老年2型糖尿病大鼠记忆的改善作用。将大鼠随机分为对照组,老年群体,老年T2DM模型组,TP75、150、300mg/kg组。TP300mg/kg通过降低p-mTOR（S2448）的水平改善线粒体自噬，P62和HSP60，增加PINK1和Parkin的水平，LC3Ⅱ/LC3Ⅰ的比值,LC3和HSP60的共定位以及自噬体或自溶酶体的数量。TP300mg/kg通过下调p-PERK的水平来减轻ERS，p-eIF2α，ATF4、GRP78和恢复ER结构。为了进一步验证表没食子儿茶素没食子酸酯（EGCG），它是TP的主要活性成分，通过抑制ERS增强线粒体自噬，用ERS激活剂衣霉素(TM)或ERS抑制剂4-苯基丁酸(4-PBA)预处理PC12细胞。结果表明，EGCG对线粒体自噬的改善被TM抑制，4-PBA促进。总的来说，海马神经元的ERS-线粒体自噬在TP改善老年2型糖尿病大鼠记忆中起关键作用。本研究将为预防老年2型糖尿病患者记忆力下降提供新的视角和策略。
