Long-term treatment with intranasal insulin ameliorates cognitive impairment, tau hyperphosphorylation, and microglial activation in a streptozotocin-induced Alzheimer's rat model.
Long-term treatment with intranasal insulin ameliorates cognitive impairment, tau hyperphosphorylation, and microglial activation in a streptozotocin-induced Alzheimer's rat model.
复制标题
长期鼻内胰岛素治疗可改善链脲佐菌素诱导的阿尔茨海默病大鼠模型中的认知障碍、tau 蛋白过度磷酸化和小胶质细胞激活
DOI：
10.1038/srep45971
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发表时间：
2017-04-06
影响因子：
4.6
通讯作者：
Zhang B
中科院分区：
文献类型：
--
作者：
Guo Z;Chen Y;Mao YF;Zheng T;Jiang Y;Yan Y;Yin X;Zhang B
最近的证据表明，脑内胰岛素信号的异常在阿尔茨海默病(AD)的发病机制中起着重要作用。据报道，鼻腔注射胰岛素可以改善健康受试者和AD患者的记忆力和注意力。然而，其潜在的分子机制却知之甚少。在这里，我们对常用的散发性AD动物模型--脑室注射链脲佐菌素的大鼠进行了连续6周的连续6周的胰岛素鼻腔注射(2 U/d)，然后用Morris水迷宫实验研究了它们的认知功能，并用Western blotting研究了它们的生化变化。我们观察了ICV-STZ大鼠的认知障碍、tau过度磷酸化和神经炎症。胰岛素滴鼻治疗6周可显著改善ICV-STZ大鼠的认知功能，降低tau蛋白过度磷酸化水平，改善小胶质细胞活化，促进神经发生。此外，我们的结果表明，鼻腔给药可能通过下调ICV-STZ大鼠脑内ERK1/2和CaMKII的表达来减轻tau的过度磷酸化。我们的研究结果证明了鼻用胰岛素的有益效果，为鼻用胰岛素治疗AD患者提供了机制基础。
Recent evidence reveals that aberrant brain insulin signaling plays an important role in the pathology of Alzheimer’s disease (AD). Intranasal insulin administration has been reported to improve memory and attention in healthy participants and in AD patients. However, the underlying molecular mechanisms are poorly understood. Here, we treated intracerebroventricular streptozotocin-injected (ICV-STZ) rats, a commonly used animal model of sporadic AD, with daily intranasal delivery of insulin (2 U/day) for 6 consecutive weeks and then studied their cognitive function with the Morris water maze test and biochemical changes via Western blotting. We observed cognitive deficits, tau hyperphosphorylation, and neuroinflammation in the brains of ICV-STZ rats. Intranasal insulin treatment for 6 weeks significantly improved cognitive function, attenuated the level of tau hyperphosphorylation, ameliorated microglial activation, and enhanced neurogenesis in ICV-STZ rats. Additionally, our results indicate that intranasal delivery of insulin probably attenuates tau hyperphosphorylation through the down-regulation of ERK1/2 and CaMKII in the brains of ICV-STZ rats. Our findings demonstrate a beneficial effect of intranasal insulin and provide the mechanistic basis for treating AD patients with intranasal insulin.