Ma He, Chang Zhenghui, Sun Hongyu, Ma Dongrui, Li Zhonghua, Hao Li, Zhang Zhenqiang, Hölscher Christian, Zhang Zijuan
School of Medical Sciences, Academy of Chinese Medical Sciences, Shangzhen Academy, Henan University of Chinese Medicine, Zhengzhou, 450046, Henan Province, China.
Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou, 450046, Henan Province, China.
Mol Neurobiol. 2025 May 8. doi: 10.1007/s12035-025-05037-7.
Glucagon-like peptide 1 (GLP-1) is a peptide hormone and growth factor. Cholecystokinin (CCK) is another peptide hormone, growth factor and neurotransmitter. Both peptide hormones have shown good neuroprotective effects in animal models of Alzheimer's disease (AD). In this study, we tested the effects of a dual GLP-1/CCK (25 nmol/kg ip. for 14 days) receptor agonist that had previously shown good effects in animal models of diabetes. The GLP-1 analogue Liraglutide (50 nmol/kg ip.) was used as a positive control. Memory was improved in the water maze and the Y-maze, spontaneous activity was increased, the chronic inflammation response had been reduced and levels of NLRP3, IL-10 and TNFα were brought back to physiological levels. Levels of amyloid aggregates in the brain were reduced by the drugs. The expression of proteins SIRPα and CD47 which is related to reduced inflammation levels was reduced. Importantly, growth factor signalling was much improved and growth levels of BDNF, TrkB receptor, p-CREB, and an upregulation of the PI3K-AKT signalling pathway had been observed. Post-synaptic density protein (PSD) and synaptophysin levels were reduced, too. In transmission electron microscope analysis, the synaptic cleft was found to be wider in 5xFAD mice. In Golgi stain evaluations, synapse numbers were brought back to normal levels by the drugs. In a direct comparison with Liraglutide, the dual GLP-1/CCK receptor agonist was superior in the water maze tests and in the upregulation of BDNF and TrkB levels in the brain. In other parameters, the dual agonist and Liraglutide showed comparable effects. In conclusion, the combination of GLP-1 and CCK receptor activation did not show overall improvements over single GLP-1 receptor activation.
胰高血糖素样肽1（GLP-1）是一种肽类激素和生长因子。胆囊收缩素（CCK）是另一种肽类激素、生长因子和神经递质。这两种肽类激素在阿尔茨海默病（AD）动物模型中均显示出良好的神经保护作用。在本研究中，我们测试了一种双重GLP-1/CCK（25 nmol/kg腹腔注射，持续14天）受体激动剂的效果，该激动剂先前在糖尿病动物模型中显示出良好效果。GLP-1类似物利拉鲁肽（50 nmol/kg腹腔注射）用作阳性对照。在水迷宫和Y迷宫中记忆得到改善，自发活动增加，慢性炎症反应减轻，NLRP3、IL-10和TNFα水平恢复到生理水平。药物降低了大脑中淀粉样蛋白聚集体的水平。与炎症水平降低相关的蛋白质SIRPα和CD47的表达减少。重要的是，生长因子信号传导显著改善，观察到脑源性神经营养因子（BDNF）、酪氨酸激酶受体B（TrkB）、磷酸化环磷腺苷反应元件结合蛋白（p-CREB）的生长水平以及磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-AKT）信号通路的上调。突触后致密蛋白（PSD）和突触素水平也降低。在透射电子显微镜分析中，发现5xFAD小鼠的突触间隙更宽。在高尔基染色评估中，药物使突触数量恢复到正常水平。在与利拉鲁肽的直接比较中，双重GLP-1/CCK受体激动剂在水迷宫测试以及大脑中BDNF和TrkB水平的上调方面更具优势。在其他参数方面，双重激动剂和利拉鲁肽显示出相当的效果。总之，与单一GLP-1受体激活相比，GLP-1和CCK受体激活的联合应用并未显示出整体改善。
