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Dendrobium nobile Lindl alkaloid and metformin ameliorate cognitive dysfunction in senescence-accelerated mice via suppression of endoplasmic reticulum stress.
Brain Research ( IF 2.7 ) Pub Date : 2020-05-04 , DOI: 10.1016/j.brainres.2020.146871
Bo Liu 1 , Bo Huang 2 , Jie Liu 2 , Jing-Shan Shi 2
Affiliation  

The senescence-accelerated mouse prone 8 (SAMP8) mice have many pathological features of Alzheimer's disease (AD) with aging. We previously reported that Dendrobium nobile Lindl alkaloid (DNLA) effectively improved cognitive deficits in multiple Alzheimer's disease (AD) models. This study further used SAMP8 mice to study the anti-aging effects of DNLA, focusing on endoplasmic reticulum (ER) stress. DNLA and metformin were orally administered to SAMP8 mice starting at 4-month of age for 6 months. Behavioral tests were performed in 10-month-old SAMP8 mice and age-matched SAMR1 control mice. At the end of experiment, neuron damage was evaluated by histology and transmission electron microscopy. ER stress-related proteins were analyzed with Western-blot. DNLA improved learning and memory impairments, reduced the loss of neurons and Nissl bodies in the hippocampus and cortex. DNLA ameliorated ER dilation and swelling in the hippocampal neurons. DNLA down-regulated the protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway, decreased calpain 1, GSK-3β and Cdk5 activities and the Tau hyper-phosphorylation. The effects of DNLA were comparable to metformin. In summary, DNLA was effective in improving cognitive deficits in aged SAMP8 mice, possibly via suppression of ER stress-related PERK signaling pathway, sequential inhibition of calpain 1, GSK-3β and Cdk5 activities, and eventually reducing the hyper-phosphorylation of Tau.

中文翻译:

Dendrobium nobile Lindl 生物碱和二甲双胍通过抑制内质网应激改善衰老加速小鼠的认知功能障碍。

加速衰老的小鼠俯卧 8 (SAMP8) 小鼠具有阿尔茨海默病 (AD) 与衰老的许多病理特征。我们之前曾报道,石斛 Lindl 生物碱 (DNLA) 可有效改善多种阿尔茨海默病 (AD) 模型中的认知缺陷。本研究进一步使用 SAMP8 小鼠来研究 DNLA 的抗衰老作用,重点是内质网 (ER) 应激。从 4 月龄开始向 SAMP8 小鼠口服 DNLA 和二甲双胍,持续 6 个月。在 10 个月大的 SAMP8 小鼠和年龄匹配的 SAMR1 对照小鼠中进行了行为测试。在实验结束时,通过组织学和透射电子显微镜评估神经元损伤。用蛋白质印迹分析内质网应激相关蛋白。DNLA 改善学习和记忆障碍,减少海马和皮层中神经元和尼氏体的损失。DNLA 改善了海马神经元的 ER 扩张和肿胀。DNLA 下调蛋白激酶 RNA 样内质网激酶 (PERK) 信号通路,降低钙蛋白酶 1、GSK-3β 和 Cdk5 活性以及 Tau 过度磷酸化。DNLA 的作用与二甲双胍相当。总之,DNLA 可有效改善老年 SAMP8 小鼠的认知缺陷,这可能是通过抑制内质网应激相关的 PERK 信号通路,顺序抑制钙蛋白酶 1、GSK-3β 和 Cdk5 活性,并最终降低 Tau 的过度磷酸化。DNLA 下调蛋白激酶 RNA 样内质网激酶 (PERK) 信号通路,降低钙蛋白酶 1、GSK-3β 和 Cdk5 活性以及 Tau 过度磷酸化。DNLA 的作用与二甲双胍相当。总之,DNLA 可有效改善老年 SAMP8 小鼠的认知缺陷,这可能是通过抑制内质网应激相关的 PERK 信号通路,顺序抑制钙蛋白酶 1、GSK-3β 和 Cdk5 活性,并最终降低 Tau 的过度磷酸化。DNLA 下调蛋白激酶 RNA 样内质网激酶 (PERK) 信号通路,降低钙蛋白酶 1、GSK-3β 和 Cdk5 活性以及 Tau 过度磷酸化。DNLA 的作用与二甲双胍相当。总之,DNLA 可有效改善老年 SAMP8 小鼠的认知缺陷,这可能是通过抑制内质网应激相关的 PERK 信号通路,顺序抑制钙蛋白酶 1、GSK-3β 和 Cdk5 活性,并最终降低 Tau 的过度磷酸化。
更新日期:2020-05-04
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