Yin Rong, Yin Kai, Guo ZhiQiang, Zhang ZhiQiang, Chen LiPin, Cao Li, Li YuanMin, Wei YaXuan, Fu XueFeng, Shi XiangQun
Cell Physiol Biochem. 2016;38(3):1138-46. doi: 10.1159/000443064. Epub 2016 Mar 11.
Alzheimer's disease (AD) is characterized with progressive memory loss and severe cognitive impairments, which affect everyday life and human health in the elderly. It is required that an effective and safe protective reagent against AD should be developed. It has been reported that humanin (HN) exerts neuroprotective effects against AD. In this study, we investigated the effect of a novel and more effective HN derivative, Colivelin (CLN) on AD.
PDAPP(V717I) transgenic AD model mice (derived from parental C57/BL6 mice) were used in our study as AD model. Morris water maze test was used to test the memory impairment of AD mice and the levels of Aβ40 and Aβ42 were determined by an Elisa assay. We used an Immunohistochemistry and Immunofluorescence staining method to check the GFAP and MAP2 positive cells, and TUNEL to assess the apoptotic cells. Western blot assay was used to check the expression and phosphorylation level of p38.
We found that CLN improved the memory impairment induced by AD and reduced the deposit of Aβ40 and Aβ42. CLN also inhibited cell apoptosis and activation of caspase 3 in brain tissues of AD mice. Inflammation in AD mice was alleviated by CLN treatment, including the accumulation of GFAP positive cells and the inflammatory cytokines. With both structure of AGA-HNG and ANDF, CLN exhibited significantly stronger effects than synchronously administration of AGA-HNG and ADNF, suggesting CLN as a novel potential effective therapeutic reagent for AD patients. Finally, we found that CLN inhibited phosphorylation of p38 in AD mice and p38 inhibitor, SB203580 weakened the therapeutic effect of CLN.
CLN effectively improved the memory dysfunction in PDAPP mice, and our data suggests CLN as a novel and effective reagent which may have great potentials in AD therapy.
阿尔茨海默病（AD）的特征是进行性记忆丧失和严重的认知障碍，这会影响老年人的日常生活和健康。因此，需要开发一种有效且安全的针对AD的保护试剂。据报道，人胰岛素（HN）对AD具有神经保护作用。在本研究中，我们研究了一种新型且更有效的HN衍生物Colivelin（CLN）对AD的影响。
我们使用源自亲代C57/BL6小鼠的PDAPP（V717I）转基因AD模型小鼠作为AD模型。采用Morris水迷宫试验检测AD小鼠的记忆障碍，并通过酶联免疫吸附测定法测定Aβ40和Aβ42的水平。我们使用免疫组织化学和免疫荧光染色方法检查GFAP和MAP2阳性细胞，并使用TUNEL法评估凋亡细胞。采用蛋白质免疫印迹法检测p38的表达和磷酸化水平。
我们发现CLN改善了AD诱导的记忆障碍，并减少了Aβ40和Aβ42的沉积。CLN还抑制了AD小鼠脑组织中的细胞凋亡和半胱天冬酶3的激活。CLN治疗减轻了AD小鼠的炎症，包括GFAP阳性细胞的积累和炎性细胞因子。与AGA-HNG和ANDF的结构相比，CLN表现出比同时给予AGA-HNG和ADNF更强的效果，表明CLN是一种对AD患者具有潜在疗效的新型试剂。最后，我们发现CLN抑制了AD小鼠中p38的磷酸化，并且p38抑制剂SB203580削弱了CLN的治疗效果。
CLN有效改善了PDAPP小鼠的记忆功能障碍，我们的数据表明CLN是一种新型有效试剂，在AD治疗中可能具有巨大潜力。
