Agmatine ameliorates type 2 diabetes induced-Alzheimer's disease-like alterations in high-fat diet-fed mice via reactivation of blunted insulin signalling
Agmatine ameliorates type 2 diabetes induced-Alzheimer's disease-like alterations in high-fat diet-fed mice via reactivation of blunted insulin signalling
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DOI：
10.1016/j.neuropharm.2016.10.029
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发表时间：
2017-02-01
影响因子：
4.7
通讯作者：
Lee, Jong Eun
中科院分区：
文献类型：
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作者：
Kang, Somang;Kim, Chul-Hoon;Lee, Jong Eun
2型糖尿病（T2 DM）患者患阿尔茨海默病（AD）的风险更高。先前在高脂饮食诱导的AD动物模型中的研究表明，这些动物的脑胰岛素抵抗导致淀粉样蛋白β（A β）的积累和GSK-3 β磷酸化的减少，后者促进tau磷酸化导致AD。尚未发现针对T2 DM患者的AD的治疗方法。胍丁胺是从L-精氨酸衍生的一种伯胺，在糖尿病动物中表现出抗糖尿病作用。本研究旨在探讨胍丁胺对脑胰岛素抵抗所致AD的治疗作用。ICR小鼠喂食60%高脂饲料12周，并在饲料中注射一次链脲佐菌素（100 mg/kg/ip）4周。在12周的饮食后，小鼠用胍丁胺（100 mg/kg/ip）处理2周。在处死前进行行为测试。评价胰岛素信号分子p-IRS-1、p-Akt和p-GSK-3 β的脑表达水平以及A β和p-tau的蓄积。胍丁胺给药挽救了胰岛素信号传导的减少，这反过来又减少了A β和p-tau在大脑中的积累。此外，胍丁胺治疗也减少了认知能力下降。胍丁胺通过激活胰岛素信号的钝化而减轻T2 DM小鼠AD的发生。(C)2016作者爱思唯尔有限公司出版
The risk of Alzheimer's disease (AD) is higher in patients with type 2 diabetes mellitus (T2DM). Previous studies in high-fat diet-induced AD animal models have shown that brain insulin resistance in these animals leads to the accumulation of amyloid beta (A beta) and the reduction in GSK-3 beta phosphorylation, which promotes tau phosphorylation to cause AD. No therapeutic treatments that target AD in T2DM patients have yet been discovered. Agmatine, a primary amine derived from L-arginine, has exhibited anti-diabetic effects in diabetic animals. The aim of this study was to investigate the ability of agmatine to treat AD induced by brain insulin resistance. ICR mice were fed a 60% high-fat diet for 12 weeks and received one injection of streptozotocin (100 mg/kg/ip) 4 weeks into the diet. After the 12-week diet, the mice were treated with agmatine (100 mg/kg/ip) for 2 weeks. Behaviour tests were conducted prior to sacrifice. Brain expression levels of the insulin signal molecules p-IRS-1, p-Akt, and p-GSK-3 beta and the accumulation of A beta and p-tau were evaluated. Agmatine administration rescued the reduction in insulin signalling, which in turn reduced the accumulation of A beta and p-tau in the brain. Furthermore, agmatine treatment also reduced cognitive decline. Agmatine attenuated the occurrence of AD in T2DM mice via the activation of the blunted insulin signal. (C) 2016 The Authors. Published by Elsevier Ltd.