a Department of Anatomy , Basic Medical College of Nanchang University , Nanchang , China.
b Department of Neurology , Second Affiliated Hospital of Nanchang University , Nanchang , China.
Pharm Biol. 2019 Dec;57(1):453-459. doi: 10.1080/13880209.2019.1629463.
Neuroligin-1 (NLGN1) is a cell adhesion protein located on the excitatory postsynaptic membrane. β-Amyloid (Aβ)-induced neuroinflammation decreases NLGN1 expression through epigenetic mechanisms. Triptolide (T10) and tripchlorolide (T4) exert protective effects on synapses in Alzheimer's disease (AD) mice, but the mechanisms remain unclear. The effects of T10 and T4 on hippocampal NLGN1 expression in AD mice and the epigenetic mechanisms were assessed using chromatin immunoprecipitation and methylated DNA immunoprecipitation. Sixty APP/PS1 transgenic mice were randomly divided into an AD model group, a T10-treated group and a T4-treated group ( = 20); 20 wild-type littermates served as the control group. APP/PS1 transgenic mice were intraperitoneally injected with T10 (0.1 mg/kg) and T4 (25 μg/kg) once per day for 60 days. NLGN1 expression was examined using western blotting and quantitative PCR. T10 and T4 increased the levels of the NLGN1 protein and mRNA in hippocampus of AD mice. T10 and T4 inhibited the binding of HDAC2 (< 0.01) and MeCP2 (< 0.01 and < 0.05, respectively) to the NLGN1 promoter, and cytosine methylation (1.2305 ± 0.1482/1.2554 ± 0.3570 vs. 1.6578 ± 0.1818, < 0.01) at the NLGN1 promoter in the hippocampus of AD mice. T10 and T4 increased the level of acetylated histone H3 (0.7733 ± 0.1611/0.8241 ± 0.0964 vs. 0.5587 ± 0.0925, < 0.01) at the NLGN1 promoter in the hippocampus of AD mice. T10 and T4 may increase hippocampal NLGN1 expression in AD mice through epigenetic mechanisms, providing a new explanation for the mechanism underlying the protective effects of T10 and T4 on synapses.
神经黏附素 1（NLGN1）是一种位于兴奋性突触后膜的细胞黏附蛋白。β-淀粉样蛋白（Aβ）诱导的神经炎症通过表观遗传机制降低 NLGN1 的表达。雷公藤内酯醇（T10）和雷公藤甲素（T4）对阿尔茨海默病（AD）小鼠的突触具有保护作用，但机制尚不清楚。本研究采用染色质免疫沉淀和甲基化 DNA 免疫沉淀技术，评估 T10 和 T4 对 AD 小鼠海马 NLGN1 表达的影响及其表观遗传机制。将 60 只 APP/PS1 转基因小鼠随机分为 AD 模型组、T10 治疗组和 T4 治疗组（每组 20 只）；20 只野生型同窝仔鼠作为对照组。APP/PS1 转基因小鼠每天腹腔注射 T10（0.1mg/kg）和 T4（25μg/kg），连续 60 天。采用 Western blot 和 qPCR 检测 NLGN1 表达。结果显示，T10 和 T4 增加了 AD 小鼠海马 NLGN1 蛋白和 mRNA 水平。T10 和 T4 抑制了 HDAC2（<0.01）和 MeCP2（<0.01 和 <0.05）与 NLGN1 启动子的结合，并抑制了 AD 小鼠海马 NLGN1 启动子上的胞嘧啶甲基化（1.2305±0.1482/1.2554±0.3570 比 1.6578±0.1818，<0.01）。T10 和 T4 增加了 AD 小鼠海马 NLGN1 启动子上组蛋白 H3 乙酰化水平（0.7733±0.1611/0.8241±0.0964 比 0.5587±0.0925，<0.01）。综上，T10 和 T4 可能通过表观遗传机制增加 AD 小鼠海马 NLGN1 的表达，为 T10 和 T4 对突触的保护作用机制提供了新的解释。
