Glucagon-Like Peptide-1 Cleavage Product Improves Cognitive Function in a Mouse Model of Down Syndrome.
Glucagon-Like Peptide-1 Cleavage Product Improves Cognitive Function in a Mouse Model of Down Syndrome.
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DOI：
10.1523/eneuro.0031-19.2019
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发表时间：
2019-03-01
期刊：
影响因子：
3.4
通讯作者：
Ma, Tao
中科院分区：
文献类型：
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作者：
Day, Stephen M;Yang, Wenzhong;Ma, Tao
唐氏综合征（Down syndrome，DS）是人类最常见的与21号染色体三体相关的智力残疾形式之一，目前还没有有效的治疗方法可用于唐氏综合征（Down syndrome，DS）中的认知障碍。胰高血糖素样肽-1（GLP-1）是一种肠促胰岛素激素，通过刺激胰岛素分泌维持葡萄糖稳态。其天然裂解产物GLP-1（9-36）缺乏促胰岛素作用，对GLP-1受体的结合亲和力较低;因此，GLP-1（9-36）历来被鉴定为无活性代谢产物。相反，最近的工作已经证明了GLP-1（9-36）的有趣的生理特性，例如心脏保护和神经保护。我们之前已经证明，GLP-1（9-36）给药增强了幼年WT小鼠的神经元可塑性，并改善了阿尔茨海默病小鼠模型的认知缺陷。在此，我们报告了在任一性别的Ts 65 Dn DS模型小鼠中全身给予GLP-1（9-36）导致海马中线粒体氧化应激降低，树突棘形态改善，成熟棘增加，未成熟棘减少。重要的是，这些分子改变转化为功能变化，即TsDn 65 DS模型小鼠的长时程增强功能衰竭和认知障碍可通过GLP-1（9-36）治疗得到挽救。我们还表明，长期GLP-1（9-36）治疗不会改变WT或DS模型小鼠的葡萄糖耐量。我们的研究结果表明，GLP-1（9-36）治疗可能对DS和其他与神经元氧化应激增加相关的神经退行性疾病具有治疗潜力。
Currently there is no effective therapy available for cognitive impairments in Down syndrome (DS), one of the most prevalent forms of intellectual disability in humans associated with the chromosomes 21 trisomy. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that maintains glucose homeostasis by stimulating insulin secretion. Its natural cleavage product GLP-1 (9-36) lacks insulinotropic effects and has a low binding affinity for GLP-1 receptors; thus, GLP-1 (9-36) has historically been identified as an inactive metabolite. Conversely, recent work has demonstrated interesting physiological properties of GLP-1 (9-36) such as cardioprotection and neuroprotection. We have previously shown that GLP-1 (9-36) administration enhances neuronal plasticity in young WT mice and ameliorates cognitive deficits in a mouse model of Alzheimer's disease. Here, we report that systemic administration of GLP-1 (9-36) in Ts65Dn DS model mice of either sex resulted in decreased mitochondrial oxidative stress in hippocampus and improved dendritic spine morphology, increase of mature spines and reduction of immature spines. Importantly, these molecular alterations translated into functional changes in that long-term potentiation failure and cognitive impairments in TsDn65 DS model mice were rescued with GLP-1 (9-36) treatment. We also show that chronic GLP-1 (9-36) treatment did not alter glucose tolerance in either WT or DS model mice. Our findings suggest that GLP-1 (9-36) treatment may have therapeutic potential for DS and other neurodegenerative diseases associated with increased neuronal oxidative stress.