Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals.
Exenatide promotes cognitive enhancement and positive brain metabolic changes in PS1-KI mice but has no effects in 3xTg-AD animals.
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DOI：
10.1038/cddis.2013.139
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发表时间：
2013-05-02
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
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最近的研究表明，2型糖尿病(T2 DM)是认知功能障碍或痴呆的危险因素。胰岛素抵抗通常与T2 DM相关，可导致中枢神经系统胰岛素信号缺陷，并增加老年人认知功能障碍的风险。GLP-1是一种胰岛素样激素，与GLP-1类似物一样，能刺激胰岛素的分泌，已被用于治疗T2 DM。GLP-1和GLP-1类似物还可以增强突触的可塑性，并抵消神经元功能障碍和/或变性模型小鼠的认知缺陷。在这项研究中，我们研究了长期使用GLP-1类似物埃塞那肽对两种神经元功能障碍动物模型：PS1-KI和3xTg-AD小鼠的潜在神经保护作用。我们发现，埃塞那肽对PS1-KI的短期和长期记忆表现有促进作用，但在3xTg-AD动物中没有。在PS1-Ki小鼠中，该药物增加了脑乳酸脱氢酶的活性，导致乳酸水平的净增加，而对线粒体呼吸没有影响。而艾塞那肽对3xTg-AD小鼠脑代谢无明显影响。综上所述，我们的数据表明埃塞那肽改善了PS1-Ki小鼠的认知能力，这种作用可能是通过增加大脑的厌氧糖酵解率来实现的。
Recent studies have shown that type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction or dementia. Insulin resistance is often associated with T2DM and can induce defective insulin signaling in the central nervous system as well as increase the risk of cognitive impairment in the elderly. Glucagone like peptide-1 (GLP-1) is an incretin hormone and, like GLP-1 analogs, stimulates insulin secretion and has been employed in the treatment of T2DM. GLP-1 and GLP-1 analogs also enhance synaptic plasticity and counteract cognitive deficits in mouse models of neuronal dysfunction and/or degeneration. In this study, we investigated the potential neuroprotective effects of long-term treatment with exenatide, a GLP-1 analog, in two animal models of neuronal dysfunction: the PS1-KI and 3xTg-AD mice. We found that exenatide promoted beneficial effects on short- and long-term memory performances in PS1-KI but not in 3xTg-AD animals. In PS1-KI mice, the drug increased brain lactate dehydrogenase activity leading to a net increase in lactate levels, while no effects were observed on mitochondrial respiration. On the contrary, exenatide had no effects on brain metabolism of 3xTg-AD mice. In summary, our data indicate that exenatide improves cognition in PS1-KI mice, an effect likely driven by increasing the brain anaerobic glycolysis rate.
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