At present, few available drugs can be used to either improve pathological features or prevent the progression of Alzheimer's disease (AD). DL0410 ((1,1'-([1,1'-biphenyl]-4,4'-diyl) bis (3-(piperidin-1-yl) propan-1-one) dihydrochloride) is a multiple-target small molecule that has been found to reverse cognitive impairment in different animal models of AD. In this study we evaluated the cognition-improving effects of DL0410 in APP/PS1 transgenic mice and explored the underlying mechanisms. APP/PS1 transgenic mice were administered DL0410 (3, 10, 30 mg· kg-1· d-1, ig) for 2 months. We found that DL0410 administration significantly ameliorated cognitive deficits in both the nest-building and Morris water maze tests. In electrophysiological analysis of hippocampal slices, we showed that DL0410 administration significantly enhanced the field EPSP slope and HFS-induced LTP in CA1 area. Furthermore, we revealed that DL0410 administration significantly increased the phosphorylation of AKT and the activity of GSK-3β in the hippocampus and cortex. Moreover, DL0410 administration dose-dependently increased the expression level of phosphorylated ERK1/2 in the hippocampus and cortex. In addition, DL0410 dose-dependently decreased the neuronal loss by decreasing the production of Aβ deposition, inhibited glial overactivation, and the production of inflammatory cytokines such as TNF-α, IL-1β, and IL-6. We conclude that DL0410 ameliorates cognitive deficits in APP/PS1 transgenic mice by promoting synaptic transmission via activating the AKT/GSK-3β and MAPK/ERK signaling pathway and reducing neuronal loss. DL0410 may be an effective agent for AD treatment in the future.

中文翻译：

---

DL0410 通过促进突触传递和减少神经元损失来改善 APP/PS1 转基因小鼠的认知缺陷。

目前，很少有药物可用于改善阿尔茨海默病（AD）的病理特征或预防其进展。DL0410 ((1,1'-([1,1'-联苯]-4,4'-二基)双(3-(哌啶-1-基)丙-1-酮)二盐酸盐)是一种多靶点小分子化合物已发现该分子可以逆转不同 AD 动物模型中的认知障碍。在本研究中，我们评估了 DL0410 对 APP/PS1 转基因小鼠的认知改善作用，并探讨了其潜在机制。对 APP/PS1 转基因小鼠给予 DL0410（3 , 10, 30 mg· kg-1· d-1, ig) 2个月。我们发现DL0410给药显着改善了筑巢和莫里斯水迷宫测试中的认知缺陷。在海马切片的电生理分析中，我们显示DL0410 给药显着增强了 CA1 区的场 EPSP 斜率和 HFS 诱导的 LTP。此外，我们发现 DL0410 给药显着增加了海马和皮质中 AKT 的磷酸化以及 GSK-3β 的活性。此外，DL0410 给药剂量-依赖性增加海马和皮质中磷酸化 ERK1/2 的表达水平。此外，DL0410 通过减少 Aβ 沉积的产生、抑制神经胶质过度激活以及炎症细胞因子（如 TNF-α、IL-1β 和 IL-6）的产生，以剂量依赖性方式减少神经元损失。我们得出的结论是，DL0410 通过激活 AKT/GSK-3β 和 MAPK/ERK 信号通路促进突触传递并减少神经元损失，从而改善 APP/PS1 转基因小鼠的认知缺陷。DL0410可能成为未来治疗AD的有效药物。