Alzheimer’s disease (AD) is a neurodegenerative disorder for which there is no cure. Here, we test a dual GLP-1/GIP receptor agonist (DA4-JC) that has a cell penetrating sequence added to enhance blood-brain barrier penetration. We show in a receptor activity study that DA4-JC has balanced activity on both GLP-1 and GIP receptors but not on GLP-2 or Glucagon receptors. A dose-response study in the APP/PS1 mouse model of AD showed both a dose-dependent drug effect on the inflammation response and the reduction of amyloid plaques in the brain. When comparing DA4-JC with the GLP-1 analogue liraglutide at equal doses of 10nmol/kg bw ip. once-daily for 8 weeks, DA4-JC was more effective in reversing memory loss, enhancing synaptic plasticity (LTP) in the hippocampus, reducing amyloid plaques and lowering pro-inflammatory cytokine levels in the brain. The results suggest that DA4-JC may be a novel treatment for AD.

阿尔茨海默病（AD）是一种神经退行性疾病，无法治愈。在这里，我们测试了一种双重 GLP-1/GIP 受体激动剂 (DA4-JC)，它添加了细胞穿透序列以增强血脑屏障的穿透性。我们在一项受体活性研究中表明，DA4-JC 对 GLP-1 和 GIP 受体具有平衡活性，但对 GLP-2 或胰高血糖素受体没有平衡活性。在 AD 的 APP/PS1 小鼠模型中进行的剂量反应研究表明，药物对炎症反应和大脑中淀粉样斑块的减少具有剂量依赖性的作用。当将 DA4-JC 与 GLP-1 类似物利拉鲁肽以 10nmol/kg bw ip 等剂量进行比较时。每天一次，持续 8 周，DA4-JC 在逆转记忆丧失、增强海马突触可塑性 (LTP)、减少淀粉样斑块和降低大脑中促炎细胞因子水平方面更有效。结果表明 DA4-JC 可能是治疗 AD 的一种新方法。