DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer's disease
DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer's disease
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DOI：
10.1016/j.ejphar.2018.03.024
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发表时间：
2018-05-15
影响因子：
5
通讯作者：
Qi, Jin-Shun
中科院分区：
文献类型：
--
作者：
Cao, Yue;Holscher, Christian;Qi, Jin-Shun
阿尔茨海默病（AD）是一种进行性神经退行性疾病，目前尚无治愈方法。AD的早期首发症状是记忆能力下降，逐渐发展为完全性痴呆。2型糖尿病（T2 DM）是AD的重要危险因素;开发用于治疗糖尿病的肠促胰岛素激素GLP-1的模拟物正在作为AD的新治疗策略进行测试。在本研究中，我们首次报道了一种新型GLP-1/GIP双重激动剂DA 5-CH在APP/PS1转基因AD小鼠模型中激活肠促胰岛素激素GLP-1和GIP受体的神经保护作用。我们发现：（1）DA 5-CH能有效改善9月龄AD小鼠Y迷宫和Morris水迷宫实验中的工作记忆和长时空间记忆，（2）能降低海马淀粉样老年斑和磷酸化tau蛋白水平，（3）能基本逆转海马晚相长时程增强功能的缺陷，（4）能显著改善AD小鼠海马神经元的长时程增强功能。（4）DA 5-CH可上调APP/PS 1小鼠海马中p-PI 3 K和p-AKT生长因子激酶的水平，并抑制p-GSK 3 β的过度激活。因此，DA 5-CH减轻认知障碍和病理损伤的神经保护作用可能与改善海马突触可塑性和激活PI 3 K/AKT信号通路有关。我们认为DA 5-CH可能有益于AD患者的治疗，尤其是合并T2 DM或高血糖的患者。
Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is no cure. The early primary symptom of AD is the decline of memory ability, which gradually develops into complete dementia. Type 2 diabetes mellitus (T2DM) is an important risk factor of AD; and mimetics of the incretin hormone GLP-1 developed to treat diabetes are being tested as a novel therapeutic strategy for AD. In the present study, we reported for the first time the neuroprotective effects of a novel GLP-1/GIP dual agonist DA5-CH that activates the incretin hormone GLP-1 and GIP receptors in the APP/PS1 transgenic AD mouse model. We found that: (1) DA5-CH administration effectively improved working-memory and long-term spatial memory of 9-month-old AD mice in Y-maze and Morris water maze tests; (2) DA5-CH also reduced hippocampal amyloid senile plaques and phosphorylated tau protein levels; (3) DA5-CH basically reversed the deficits in hippocampal late-phase long-term potentiation; (4) DA5-CH up-regulated the levels of p-PI3K and p-AKT growth factor kinases and prevented excessive activation of p-GSK3 beta in the hippocampus of APP/PS1 mice. Therefore, the neuroprotection of DA5-CH in alleviating cognitive impairments and pathological damages might be associated with the improvement of hippocampal synaptic plasticity and activation of the PI3K/AKT signaling pathway. We propose that DA5-CH may be beneficial for the treatment of AD patients, especially those with T2DM or hyperglycemia.