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The diabetes drug Liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease

机译:糖尿病药物利拉鲁肽可预防阿尔茨海默氏病小鼠模型的退化过程

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摘要

Type 2 diabetes is a risk factor for Alzheimer's disease, most likely linked to an impairment of insulin signaling in the brain. The incretin hormone glucagon-like peptide-1 (GLP-1) facilitates insulin signaling, and novel long-lasting GLP-1 analogs, such as liraglutide, are on the market as diabetes therapeutics. GLP-1 has been shown to have neuroprotective properties in vitro and in vivo. Here we tested the effects of peripherally injected liraglutide in an Alzheimer mouse model, APPswe/PS1ΔE9 (APP/PS1). Liraglutide was shown to cross the blood–brain barrier in an acute study. Liraglutide was injected for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old APP/PS1 and wild-type littermate controls. In APP/PS1 mice, liraglutide prevented memory impairments in object recognition and water maze tasks, and prevented synapse loss and deterioration of synaptic plasticity in the hippocampus, commonly observed in this model. Overall β-amyloid plaque count in the cortex and dense-core plaque numbers were reduced by 40–50%, while levels of soluble amyloid oligomers were reduced by 25%. The inflammation response as measured by activated microglia numbers was halved in liraglutide-treated APP/PS1 mice. Numbers of young neurons in the dentate gyrus were increased in APP/PS1 mice with treatment. Liraglutide treatment had little effect on littermate control mice, whose behavior was comparable to wild-type saline controls; however, synaptic plasticity was enhanced in the drug group. Our results show that liraglutide prevents key neurodegenerative developments found in Alzheimer's disease, suggesting that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.
机译:2型糖尿病是阿尔茨海默氏病的危险因素,最有可能与大脑中胰岛素信号转导受损有关。肠降血糖素激素胰高血糖素样肽-1(GLP-1)促进胰岛素信号传导,新型长效GLP-1类似物(如利拉鲁肽)已在市场上作为糖尿病治疗药物。已经显示GLP-1在体外和体内具有神经保护特性。在这里,我们测试了在Alzheimer小鼠模型APPswe /PS1ΔE9(APP / PS1)中外围注射利拉鲁肽的作用。在一项急性研究中显示利拉鲁肽可穿过血脑屏障。利拉鲁肽以25 nmol / kg体重i.p.注射8周。每天一次,在7个月大的APP / PS1和野生型同窝仔对照中。在APP / PS1小鼠中,利拉鲁肽预防了对象识别和水迷宫任务中的记忆障碍,并防止了海马突触的丢失和突触可塑性的恶化(通常在该模型中观察到)。皮质中的整体β淀粉样蛋白斑块和致密核心斑块数减少了40%至50%,而可溶性淀粉样蛋白低聚物的水平减少了25%。通过利拉鲁肽治疗的APP / PS1小鼠,通过激活的小胶质细胞数量测得的炎症反应减半。经治疗的APP / PS1小鼠的齿状回中年轻的神经元数量增加。利拉鲁肽治疗对同窝对照小鼠几乎没有影响,其行为与野生型盐水对照相当。但是,该药物组的突触可塑性增强了。我们的结果表明,利拉鲁肽可预防阿尔茨海默氏病的关键神经退行性发展,这表明GLP-1类似物代表了一种新型的阿尔茨海默氏病治疗策略。

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