Our previous data indicated that tanshinone IIA (tan IIA) improves learning and memory in a mouse model of Alzheimer's disease (AD) induced by streptozotocin via restoring cholinergic function, attenuating oxidative stress and blocking p38 MAPK signal pathway activation. This study aims to estimate whether tan IIA inhibits endoplasmic reticulum (ER) stress-induced apoptosis to prevent cognitive decline in APP/PS1 transgenic mice. Tan IIA (10 mg/kg and 30 mg/kg) was intraperitoneally administered to the six-month-old APP/PS1 mice for 30 consecutive days. β-amyloid (Aβ) plaques were measured by immunohistochemisty and Thioflavin S staining, apoptotic cells were observed by TUNEL, ER stress markers and apoptosis signaling proteins were investigated by western blotting and RT-PCR. Our results showed that tan IIA significantly ameliorates cognitive deficits and improves spatial learning ability of APP/PS1 mice in the nest-building test, novel object recognition test and Morris water maze test. Furthermore, tan IIA significantly reduced the deposition of Aβ plaques and neuronal apoptosis, and markedly prevented abnormal expression of glucose regulated protein 78 (GRP78), initiation factor 2α (eIF2α), inositol-requiring enzyme 1α (IRE1α), activating transcription factor 6 (ATF6), as well as suppressed the activation of C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) pathways in the parietal cortex and hippocampus. Moreover, tan IIA induced an up-regulation of the Bcl-2/Bax ratio and down-regulation of caspase-3 protein activity. Taken together, the above findings indicated that tan IIA improves learning and memory through attenuating Aβ plaques deposition and inhibiting ER stress-induced apoptosis. These results suggested that tan IIA might become a promising therapeutic candidate drug against AD.

中文翻译：

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丹参酮IIA通过抑制内质网应激诱导的APP / PS1转基因小鼠的凋亡来改善认知功能障碍。

我们以前的数据表明，丹参酮IIA（tan IIA）可通过恢复胆碱能功能，减轻氧化应激并阻止p38 MAPK信号通路激活来改善链脲佐菌素诱发的阿尔茨海默氏病（AD）小鼠模型的学习和记忆。这项研究旨在估计棕褐色IIA是否抑制内质网（ER）应激诱导的细胞凋亡，以防止APP / PS1转基因小鼠的认知能力下降。连续30天向6个月大的APP / PS1小鼠腹膜内施用Tan IIA（10 mg / kg和30 mg / kg）。免疫组织化学和硫黄素S染色检测β淀粉样蛋白斑块，TUNEL观察凋亡细胞，Western blotting和RT-PCR研究ER应激标志物和凋亡信号蛋白。我们的研究结果表明，棕褐色IIA在筑巢测试，新型物体识别测试和莫里斯水迷宫测试中可显着改善APP / PS1小鼠的认知缺陷并提高其空间学习能力。此外，tan IIA显着减少了Aβ斑块的沉积和神经元凋亡，并显着防止了葡萄糖调节蛋白78（GRP78），起始因子2α（eIF2α），需要肌醇的酶1α（IRE1α），激活转录因子6（ ATF6），并抑制顶叶皮质和海马中C / EBP同源蛋白（CHOP）和c-Jun N端激酶（JNK）通路的激活。此外，棕褐色IIA诱导Bcl-2 / Bax比值的上调和caspase-3蛋白活性的下调。在一起 上述发现表明，tan IIA通过减弱Aβ斑块沉积和抑制ER应激诱导的细胞凋亡来改善学习和记忆。这些结果表明，tan IIA可能成为有前途的抗AD治疗候选药物。