I 类 HDAC 抑制剂 BG45 通过 CaMKII/ITPKA/Ca2+ 信号通路减轻认知障碍,Pharmaceuticals

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I 类 HDAC 抑制剂 BG45 通过 CaMKII/ITPKA/Ca2+ 信号通路减轻认知障碍
Pharmaceuticals ( IF 4.3 ) Pub Date : 2022-11-28 , DOI: 10.3390/ph15121481
Jingyun Liu ₁ , Chenghong Zhang ₁ , Jiale Wang ₁ , Yufei Huang ₁ , Di Shen ₁ , Yingqiu Hu ₁ , Haiying Chu ₁ , Xuebin Yu ₁ , Liyuan Zhang ₁ , Haiying Ma ₁

Affiliation

阿尔茨海默病（AD）严重危害全世界老年人的健康和生命。然而，尽管做出了各种科学努力，目前还没有有效的 AD 临床治疗方案。在这项工作中，研究了 APP/PS1 转基因小鼠的原代神经元中 I 类组蛋白脱乙酰酶抑制剂 (HDACI) BG45 对突触相关蛋白的影响。结果表明，BG45可以上调原代神经元中突触结合蛋白-1（SYT-1）和神经丝轻链（NF-L）的表达。在体内，APPswe/PS1dE9 (APP/PS1) 转基因小鼠每天接受 BG45 (30 mg/kg) 治疗，持续 12 天。 BG45 治疗的 APP/PS1 小鼠的行为测试显示学习和记忆能力有所改善。 BG45可以减轻树突棘的损伤并减少Aβ的沉积。与体外结果类似，BG45治疗后前额皮质中的突触相关蛋白增加。蛋白质组学分析结果强调了接受或不接受 BG45 治疗的 APP/PS1 小鼠能量代谢和钙调蛋白调节的生物过程的差异。进一步验证表明，BG45对突触和学习记忆的影响可能涉及CaMKII/ITPKA/Ca2+通路。这些结果表明，I 类 HDACI BG45 可能是 AD 早期临床治疗的有前途的药物。

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A Class I HDAC Inhibitor BG45 Alleviates Cognitive Impairment through the CaMKII/ITPKA/Ca2+ Signaling Pathway

Alzheimer’s disease (AD) seriously endangers the health and life of elderly individuals worldwide. However, despite all scientific efforts, at the moment there are no effective clinical treatment options for AD. In this work, the effect of the class I histone deacetylase inhibitor (HDACI) BG45 on synapse-related proteins was investigated in primary neurons from APP/PS1 transgenic mice. The results showed that BG45 can upregulate the expression of synaptotagmin-1 (SYT-1) and neurofilament light chain (NF-L) in primary neurons. In vivo, the APPswe/PS1dE9 (APP/PS1) transgenic mice were treated with BG45 (30 mg/kg) daily for 12 days. Behavioral testing of BG45-treated APP/PS1 mice showed improvements in learning and memory. BG45 can alleviate damage to the dendritic spine and reduce the deposition of Aβ. Similar to the in vitro results, synapse-related proteins in the prefrontal cortex were increased after BG45 treatment. Proteomic analysis results highlighted the differences in the biological processes of energy metabolism and calmodulin regulation in APP/PS1 mice with or without BG45 treatment. Further verification demonstrated that the effect of BG45 on synapses and learning and memory may involve the CaMKII/ITPKA/Ca2+ pathway. These results suggest that class I HDACI BG45 might be a promising drug for the early clinical treatment of AD.

更新日期：2022-11-28

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