Early intervention with glucagon-like peptide 1 analog liraglutide prevents tau hyperphosphorylation in diabetic db/db mice
Early intervention with glucagon-like peptide 1 analog liraglutide prevents tau hyperphosphorylation in diabetic db/db mice
复制标题
使用胰高血糖素样肽 1 类似物利拉鲁肽进行早期干预可预防糖尿病 db/db 小鼠的 tau 蛋白过度磷酸化。
DOI：
10.1111/jnc.13248
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发表时间：
2015-10-01
影响因子：
4.7
通讯作者：
Yang, Yan
中科院分区：
文献类型：
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作者：
Ma, De-Lin;Chen, Fu-Qiong;Yang, Yan
越来越多的证据表明，2型糖尿病（T2 D）是阿尔茨海默病的危险因素。由过度磷酸化的tau蛋白和错误折叠的微管组成的神经元缠结是阿尔茨海默病的神经病理学标志之一。Db/db小鼠是T2 D的啮齿动物模型，也表现出年龄依赖性tau过度磷酸化。胰高血糖素样肽-1（GLP-1）模拟物，一种用于T2 D的药物，已被发现具有神经保护作用。本研究的目的是探索利拉鲁肽（GLP-1类似物）或胰岛素对T2 D动物中tau磷酸化的潜在影响。雄性db/db小鼠（3- 3.5周龄）每日皮下注射利拉鲁肽（n=27）、胰岛素（n=27）或生理盐水（n=26），每2周一次处死5 - 7只小鼠，通过ELISA分析血浆和脑脊液（CSF）胰岛素水平，通过蛋白质印迹分析海马结构中的蛋白质水平。我们发现，用盐水处理的db/db小鼠表现出CSF胰岛素的年龄依赖性降低和海马tau蛋白磷酸化的增加。利拉鲁肽注射液在治疗8周结束时将CSF胰岛素逆转至接近1 mIU/L，并防止海马结构中tau蛋白的过度磷酸化。相比之下，胰岛素注射对CSF胰岛素或tau蛋白磷酸化没有影响。总之，本研究表明，早期GLP-1类似物干预预防了T2 D小鼠脑中的年龄依赖性tau过度磷酸化，可能是通过促进胰岛素信号传导途径中的顺序激活，反映在Akt的基础激活增加和糖原合成酶激酶-3 β的基础抑制。
Increasing evidence has shown that type 2 diabetes (T2D) is a risk factor for Alzheimer's disease. Neurofibrillary tangles, which consist of hyperphosphorylated tau and misfolded microtubules, is one of the neuropathological hallmarks of Alzheimer's disease. Db/db mice, a rodent model of T2D, also exhibited age-dependent tau hyperphosphorylation. Glucagon-like peptide-1 (GLP-1) mimetics, a type of drug used in T2D, has been found to have neuroprotective effects. The aim of this study was to explore the potential effects of liraglutide (a GLP-1 analog), or insulin, on tau phosphorylation in T2D animals. Male db/db mice (3-3.5weeks) were daily injected subcutaneously with liraglutide (n=27), insulin (n=27), or saline (n=26), and five to seven mice were killed every 2weeks for analysis of plasma and cerebrospinal (CSF) insulin levels by ELISA, and protein levels in the hippocampal formation by western blot. We found that db/db mice treated with saline exhibited an age-dependent decrease in CSF insulin and an increase in hippocampal tau phosphorylation. Liraglutide injection reversed the CSF insulin to similar to 1mIU/L by the end of 8weeks treatment, and prevented the hyperphosphorylation of tau protein in the hippocampal formation. By contrast, insulin injection had no effects on CSF insulin or phosphorylation of tau protein. In summary, this study indicates that early GLP-1 analog intervention prevented the age-dependent tau hyperphosphorylation in T2D mice brain, probably by facilitating sequential activation in an insulin signaling pathway reflected in increased basal activation of Akt and basal suppression of glycogen synthase kinase-3 beta.