Shi Lijuan, Zhang Zhihua, Li Lin, Hölscher Christian
Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China.
Key Laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, Shanxi, PR China.
Behav Brain Res. 2017 Jun 1;327:65-74. doi: 10.1016/j.bbr.2017.03.032. Epub 2017 Mar 23.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder, accompanied by memory loss and cognitive impairments, and there is no effective treatment for it at present. Since type 2 diabetes (T2DM) has been identified as a risk factor for AD, the incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP), promising antidiabetic agents for the treatment of type 2 diabetes, have been tested in models of neurodegenerative disease including AD and achieved good results. Here we show for the first time the potential neuroprotective effect of a novel dual GLP-1/GIP receptor agonist (DA-JC4) in the icv. streptozotocin (STZ)-induced AD rat model. Treatment with DA-JC4 (10nmol/kg ip.) once-daily for 14days after STZ intracerebroventricular (ICV) administration significantly prevented spatial learning deficits in a Y- maze test and Morris water maze tests, and decreased phosphorylated tau levels in the rat cerebral cortex and hippocampus. DA-JC4 also alleviated the chronic inflammation response in the brain (GFAP-positive astrocytes, IBA1-positive microglia). Apoptosis was reduced as shown in the reduced ratio of pro-apoptotic BAX to anti- apoptotic Bcl-2 levels. Importantly, insulin signaling was re-sensitized as evidenced by a reduction of phospho-IRS1 levels and phospho-Akt up-regulation. In conclusion, the novel dual agonist DA-JC4 shows promise as a novel treatment for sporadic AD, and reactivating insulin signaling pathways may be a key mechanism that prevents disease progression in AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，伴有记忆力丧失和认知障碍，目前尚无有效的治疗方法。由于2型糖尿病（T2DM）已被确定为AD的一个风险因素，肠促胰岛素胰高血糖素样肽1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP）作为治疗2型糖尿病的有前景的抗糖尿病药物，已在包括AD在内的神经退行性疾病模型中进行了测试，并取得了良好的效果。在此，我们首次展示了一种新型双GLP-1/GIP受体激动剂（DA-JC4）在脑室内注射链脲佐菌素（STZ）诱导的AD大鼠模型中的潜在神经保护作用。在STZ脑室内（ICV）给药后，每天一次腹腔注射DA-JC4（10nmol/kg），持续14天，显著预防了Y迷宫试验和莫里斯水迷宫试验中的空间学习缺陷，并降低了大鼠大脑皮层和海马体中磷酸化tau蛋白的水平。DA-JC4还减轻了大脑中的慢性炎症反应（GFAP阳性星形胶质细胞、IBA1阳性小胶质细胞）。凋亡减少，表现为促凋亡蛋白BAX与抗凋亡蛋白Bcl-2水平的比例降低。重要的是，胰岛素信号重新敏感化，表现为磷酸化IRS1水平降低和磷酸化Akt上调。总之，新型双激动剂DA-JC4有望成为散发性AD的新型治疗方法，重新激活胰岛素信号通路可能是预防AD疾病进展的关键机制。
