Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease
Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease
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DOI：
10.1016/j.neuropharm.2013.08.005
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发表时间：
2014-01-01
影响因子：
4.7
通讯作者：
Hoelscher, Christian
中科院分区：
文献类型：
--
作者：
McClean, Paula L.;Hoelscher, Christian
2型糖尿病是阿尔茨海默病（AD）发展的危险因素。已经表明，胰岛素信号传导在AD患者的大脑中脱敏。肠促胰岛素激素胰高血糖素样肽-1（GLP-1）促进胰岛素信号传导，长效类似物如利拉鲁肽（Victoza（R））作为2型糖尿病治疗药物上市。我们之前已经证明，在7个月大的APPswe/PS1 Delta E9（APP/PS1）小鼠中，当外周注射利拉鲁肽两个月时，利拉鲁肽改善了认知功能，减少了淀粉样斑块沉积、炎症、总体APP和寡聚体水平，并增强了LTP。这表明利拉鲁肽在AD发展的早期阶段具有预防作用。本研究调查了利拉鲁肽是否对小鼠晚期阿尔茨海默病具有恢复作用。因此，对14月龄APP/PS1和同窝对照小鼠ip注射利拉鲁肽（25 nmol/kg bw）。两个月与APP/PS1生理盐水处理小鼠相比，APP/PS1小鼠的空间记忆通过利拉鲁肽处理得到改善。整体斑块负荷减少了33%，炎症减少了30%，而齿状回中的神经元祖细胞计数增加了50%。与APP/PS1盐水小鼠相比，APP/PS1利拉鲁肽处理小鼠的LTP显著增强，这与海马和皮质中突触数量增加相证实。利拉鲁肽处理APP/PS1小鼠的总脑APP和β-淀粉样蛋白低聚体水平降低，而IDE水平升高。这些结果表明，利拉鲁肽不仅具有预防特性，而且还可以逆转AD的一些关键病理特征。利拉鲁肽目前正在AD患者的临床试验中进行测试。(C)2013爱思唯尔有限公司保留所有权利。
Type 2 diabetes is a risk factor in the development of Alzheimer's disease (AD). It has been shown that insulin signalling is desensitised in the brains of AD patients. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and long-lasting analogues such as liraglutide (Victoza (R)) are on the market as type 2 diabetes treatments. We have previously shown that liraglutide improved cognitive function, reduced amyloid plaque deposition, inflammation, overall APP and oligomer levels and enhanced LTP when injected peripherally for two months in 7 month old APPswe/PS1 Delta E9 (APP/PS1) mice. This showed that liraglutide has preventive effects at the early stage of AD development.The current study investigated whether Liraglutide would have restorative effects in late-stage Alzheimer's disease in mice. Accordingly, 14-month-old APP/PS1 and littermate control mice were injected with Liraglutide (25 nmol/kg bw) ip. for 2 months. Spatial memory was improved by Liraglutide-treatment in APP/PS1 mice compared with APP/PS1 saline-treated mice. Overall plaque load was reduced by 33%, and inflammation reduced by 30%, while neuronal progenitor cell count in the dentate gyrus was increased by 50%. LTP was significantly enhanced in APP/PS1 liraglutide-treated mice compared with APP/PS1 saline mice, corroborated with increased synapse numbers in hippocampus and cortex. Total brain APP and beta-amyloid oligomer levels were reduced in Liraglutide-treated APP/PS1 mice while IDE levels were increased. These results demonstrate that Liraglutide not only has preventive properties, but also can reverse some of the key pathological hallmarks of AD. Liraglutide is now being tested in clinical trials in AD patients. (C) 2013 Elsevier Ltd. All rights reserved.