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Novel Multitarget Directed Tacrine Hybrids as Anti-Alzheimer’s Compounds Improved Synaptic Plasticity and Cognitive Impairment in APP/PS1 Transgenic Mice
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-11-20 , DOI: 10.1021/acschemneuro.0c00574
Kai Li 1 , Yu Jiang 1 , Guoliang Li 2 , Tianjun Liu 2 , Zhuo Yang 1
Affiliation  

Alzheimer’s disease (AD) is a complex pathological neurodegenerative disease that seriously threatens human health. Therefore, how to effectively improve and treat AD is an urgent problem. In this study, a novel multitarget derivative based on tacrine (named 9i), which could work simultaneously on more than one pathological target, was used to treat AD model APP/PS1 transgenic mice. After 4 weeks of intragastric administration, cognitive function and synaptic plasticity were significantly improved and β-amyloid (Aβ) plaques that are main pathological hallmarks of AD were decreased in the APP/PS1 mice. On the one hand, 9i inhibited the excessive activation of the Raf/MEK/ERK signaling pathway to alleviate the loss of neurons, which provides a foundation for structural integrity. On the other hand, synaptic associated proteins and the density of synaptic spines were increased in APP/PS1 mice treated with 9i, which provides the basis for the improvement of synaptic plasticity and cognitive impairment. Interestingly, 9i also reduced Aβ plaques in the DG region, which is consistent with previous in vitro experiments showing that 9i inhibited the self-assembly of Aβ fibers, thus protecting neurons from Aβ plaque neurotoxicity. Our results suggest that 9i as a novel compound can effectively improve the cognitive function and the pathological changes of AD in APP/PS1 transgenic mice.

中文翻译:

新型多目标定向他克林杂交作为抗阿尔茨海默氏病化合物改善APP / PS1转基因小鼠的突触可塑性和认知障碍。

阿尔茨海默氏病(AD)是一种复杂的病理性神经退行性疾病,严重威胁着人类健康。因此,如何有效改善和治疗AD是当务之急。在这项研究中,基于他克林的新型多靶标衍生物(命名为9i)可以同时作用于多个病理学靶标,用于治疗AD模型APP / PS1转基因小鼠。胃内给药4周后,APP / PS1小鼠的认知功能和突触可塑性得到了显着改善,而作为AD主要病理特征的β淀粉样蛋白斑块减少了。一方面,9i抑制Raf / MEK / ERK信号通路的过度激活以减轻神经元的丢失,这为结构完整性提供了基础。另一方面,用9i处理的APP / PS1小鼠的突触相关蛋白和突触棘的密度增加,这为改善突触可塑性和认知障碍提供了基础。有趣的是,9i还减少了DG区的Aβ斑块,这与以前的体外实验一致,后者表明9i抑制了Aβ纤维的自组装,从而保护了神经元免受Aβ斑块的神经毒性。我们的结果表明9i 作为新型化合物可以有效改善APP / PS1转基因小鼠的认知功能和AD的病理变化。
更新日期:2020-12-16
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